Gene Summary

Gene:CYP1A2; cytochrome P450, family 1, subfamily A, polypeptide 2
Aliases: CP12, P3-450, P450(PA)
Summary:This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. The protein encoded by this gene localizes to the endoplasmic reticulum and its expression is induced by some polycyclic aromatic hydrocarbons (PAHs), some of which are found in cigarette smoke. The enzyme's endogenous substrate is unknown; however, it is able to metabolize some PAHs to carcinogenic intermediates. Other xenobiotic substrates for this enzyme include caffeine, aflatoxin B1, and acetaminophen. The transcript from this gene contains four Alu sequences flanked by direct repeats in the 3' untranslated region. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:cytochrome P450 1A2
Source:NCBIAccessed: 21 August, 2015


What does this gene/protein do?
Show (35)
Pathways:What pathways are this gene/protein implicaed in?
Show (5)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 21 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Transfection
  • Promoter Regions
  • Neoplasms, Experimental
  • Tissue Embedding
  • Questionnaires
  • Xanthines
  • Cytochrome P-450 CYP1A1
  • Arylamine N-Acetyltransferase
  • Phenotype
  • Practice Guidelines as Topic
  • Statistics, Nonparametric
  • Chromosome 15
  • Xenobiotics
  • Cytochrome P-450 Enzyme System
  • Thyroid Diseases
  • Cytochrome P-450 CYP1A2
  • Prostate Cancer
  • Lung Cancer
  • Spain
  • Genetic Predisposition
  • beta Carotene
  • Glutathione Transferase
  • Breast Cancer
  • Genotype
  • Risk Assessment
  • Registries
  • Risk Factors
  • CYP1B1
  • Aryl Hydrocarbon Hydroxylases
  • Single Nucleotide Polymorphism
  • Testicular Cancer
  • Colorectal Cancer
  • Tunisia
  • Estrogens
  • Case-Control Studies
  • Sweden
  • Tumor Markers
  • Urban Population
  • Smoking
Tag cloud generated 21 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CYP1A2 (cancer-related)

Hlaváč V, Brynychová V, Václavíková R, et al.
The role of cytochromes p450 and aldo-keto reductases in prognosis of breast carcinoma patients.
Medicine (Baltimore). 2014; 93(28):e255 [PubMed] Related Publications
Metabolism of anticancer drugs affects their antitumor effects. This study has investigated the associations of gene expression of enzymes metabolizing anticancer drugs with therapy response and survival of breast carcinoma patients. Gene expression of 13 aldo-keto reductases (AKRs), carbonyl reductase 1, and 10 cytochromes P450 (CYPs) was assessed using quantitative real-time polymerase chain reaction in tumors and paired adjacent nonneoplastic tissues from 68 posttreatment breast carcinoma patients. Eleven candidate genes were then evaluated in an independent series of 50 pretreatment patients. Protein expression of the most significant genes was confirmed by immunoblotting. AKR1A1 was significantly overexpressed and AKR1C1-4, KCNAB1, CYP2C19, CYP3A4, and CYP3A5 downregulated in tumors compared with control nonneoplastic tissues after correction for multiple testing. Significant association of CYP2B6 transcript levels in tumors with expression of hormonal receptors was found in the posttreatment set and replicated in the pretreatment set of patients. Significantly higher intratumoral levels of AKR1C1, AKR1C2, or CYP2W1 were found in responders to neoadjuvant chemotherapy compared with nonresponders. Patients with high AKR7A3 or CYP2B6 levels in the pretreatment set had significantly longer disease-free survival than patients with low levels. Protein products of AKR1C1, AKR1C2, AKR7A3, CYP3A4, and carbonyl reductase (CBR1) were found in tumors and those of AKR1C1, AKR7A3, and CBR1 correlated with their transcript levels. Small interfering RNA-directed knockdown of AKR1C2 or vector-mediated upregulation of CYP3A4 in MDA-MB-231 model cell line had no effect on cell proliferation after paclitaxel treatment in vitro. Prognostic and predictive roles of drug-metabolizing enzymes strikingly differ between posttreatment and pretreatment breast carcinoma patients. Mechanisms of action of AKR1C2, AKR7A3, CYP2B6, CYP3A4, and CBR1 should continue to be further followed in breast carcinoma patients and models.

Liu JB, Dai CM, Su XY, et al.
Gene microarray assessment of multiple genes and signal pathways involved in androgen-dependent prostate cancer becoming androgen independent.
Asian Pac J Cancer Prev. 2014; 15(22):9791-5 [PubMed] Related Publications
To study the gene expression change and possible signal pathway during androgen-dependent prostate cancer (ADPC) becoming androgen-independent prostate cancer (AIPC), an LNCaP cell model of AIPC was established using flutamide in combination with androgen-free environment inducement, and differential expression genes were screened by microarray. Then the biological process, molecular function and KEGG pathway of differential expression genes are analyzed by Molecule Annotation System (MAS). By comparison of 12,207 expression genes, 347 expression genes were acquired, of which 156 were up-ragulated and 191 down-regulated. After analyzing the biological process and molecule function of differential expression genes, these genes are found to play crucial roles in cell proliferation, differntiation, cell cycle control, protein metabolism and modification and other biological process, serve as signal molecules, enzymes, peptide hormones, cytokines, cytoskeletal proteins and adhesion molecules. The analysis of KEGG show that the relevant genes of AIPC transformation participate in glutathione metabolism, cell cycle, P53 signal pathway, cytochrome P450 metabolism, Hedgehog signal pathway, MAPK signal pathway, adipocytokines signal pathway, PPAR signal pathway, TGF-β signal pathway and JAK-STAT signal pathway. In conclusion, during the process of ADPC becoming AIPC, it is not only one specific gene or pathway, but multiple genes and pathways that change. The findings above lay the foundation for study of AIPC mechanism and development of AIPC targeting drugs.

Caruso JA, Campana R, Wei C, et al.
Indole-3-carbinol and its N-alkoxy derivatives preferentially target ERα-positive breast cancer cells.
Cell Cycle. 2014; 13(16):2587-99 [PubMed] Related Publications
Indole-3-carbinol (I3C) is a natural anti-carcinogenic compound found at high concentrations in Brassica vegetables. I3C was recently reported to inhibit neutrophil elastase (NE) activity, while consequently limiting the proteolytic processing of full length cyclin E into pro-tumorigenic low molecular weight cyclin E (LMW-E). In this study, we hypothesized that inhibition of NE activity and resultant LMW-E generation is critical to the anti-tumor effects of I3C. LMW-E was predominately expressed by ERα-negative breast cancer cell lines. However, ERα-positive cell lines demonstrated the greatest sensitivity to the anti-tumor effects of I3C and its more potent N-alkoxy derivatives. We found that I3C was incapable of inhibiting NE activity or the generation of LMW-E. Therefore, this pathway did not contribute to the anti-tumor activity of I3C. Gene expression analyzes identified ligand-activated aryl hydrocarbon receptor (AhR), which mediated sensitivity to the anti-tumor effects of I3C in ERα-positive MCF-7 cells. In this model system, the reactive oxygen species (ROS)-induced upregulation of ATF-3 and pro-apoptotic BH3-only proteins (e.g. NOXA) contributed to the sensitivity of ERα-positive breast cancer cells to the anti-tumor effects of I3C. Overexpression of ERα in MDA-MB-231 cells, which normally lack ERα expression, increased sensitivity to the anti-tumor effects of I3C, demonstrating a direct role for ERα in mediating the sensitivity of breast cancer cell lines to I3C. Our results suggest that ERα signaling amplified the pro-apoptotic effect of I3C-induced AhR signaling in luminal breast cancer cell lines, which was mediated in part through oxidative stress induced upregulation of ATF-3 and downstream BH3-only proteins.

Kiss I, Unger C, Huu CN, et al.
Lobatin B inhibits NPM/ALK and NF-κB attenuating anaplastic-large-cell-lymphomagenesis and lymphendothelial tumour intravasation.
Cancer Lett. 2015; 356(2 Pt B):994-1006 [PubMed] Related Publications
An apolar extract of the traditional medicinal plant Neurolaena lobata inhibited the expression of the NPM/ALK chimera, which is causal for the majority of anaplastic large cell lymphomas (ALCLs). Therefore, an active principle of the extract, the furanoheliangolide sesquiterpene lactone lobatin B, was isolated and tested regarding the inhibition of ALCL expansion and tumour cell intravasation through the lymphendothelium. ALCL cell lines, HL-60 cells and PBMCs were treated with plant compounds and the ALK inhibitor TAE-684 to measure mitochondrial activity, proliferation and cell cycle progression and to correlate the results with protein- and mRNA-expression of selected gene products. Several endpoints indicative for cell death were analysed after lobatin B treatment. Tumour cell intravasation through lymphendothelial monolayers was measured and potential causal mechanisms were investigated analysing NF-κB- and cytochrome P450 activity, and 12(S)-HETE production. Lobatin B inhibited the expression of NPM/ALK, JunB and PDGF-Rβ, and attenuated proliferation of ALCL cells by arresting them in late M phase. Mitochondrial activity remained largely unaffected upon lobatin B treatment. Nevertheless, caspase 3 became activated in ALCL cells. Also HL-60 cell proliferation was attenuated whereas PBMCs of healthy donors were not affected by lobatin B. Additionally, tumour cell intravasation, which partly depends on NF-κB, was significantly suppressed by lobatin B most likely due to its NF-κB-inhibitory property. Lobatin B, which was isolated from a plant used in ethnomedicine, targets malignant cells by at least two properties: I) inhibition of NPM/ALK, thereby providing high specificity in combating this most prevalent fusion protein occurring in ALCL; II) inhibition of NF-κB, thereby not affecting normal cells with low constitutive NF-κB activity. This property also inhibits tumour cell intravasation into the lymphatic system and may provide an option to manage this early step of metastatic progression.

Heit C, Dong H, Chen Y, et al.
Transgenic mouse models for alcohol metabolism, toxicity, and cancer.
Adv Exp Med Biol. 2015; 815:375-87 [PubMed] Free Access to Full Article Related Publications
Alcohol abuse leads to tissue damage including a variety of cancers; however, the molecular mechanisms by which this damage occurs remain to be fully understood. The primary enzymes involved in ethanol metabolism include alcohol dehydrogenase (ADH), cytochrome P450 isoform 2E1, (CYP2E1), catalase (CAT), and aldehyde dehydrogenases (ALDH). Genetic polymorphisms in human genes encoding these enzymes are associated with increased risks of alcohol-related tissue damage, as well as differences in alcohol consumption and dependence. Oxidative stress resulting from ethanol oxidation is one established pathogenic event in alcohol-induced toxicity. Ethanol metabolism generates free radicals, such as reactive oxygen species (ROS) and reactive nitrogen species (RNS), and has been associated with diminished glutathione (GSH) levels as well as changes in other antioxidant mechanisms. In addition, the formation of protein and DNA adducts associated with the accumulation of ethanol-derived aldehydes can adversely affect critical biological functions and thereby promote cellular and tissue pathology. Animal models have proven to be valuable tools for investigating mechanisms underlying pathogenesis caused by alcohol. In this review, we provide a brief discussion on several animal models with genetic defects in alcohol-metabolizing enzymes and GSH-synthesizing enzymes and their relevance to alcohol research.

Zhao PL, Zhang QF, Yan LY, et al.
Functional investigation on aromatase in endometrial hyperplasia in polycystic ovary syndrome cases.
Asian Pac J Cancer Prev. 2014; 15(20):8975-9 [PubMed] Related Publications
OBJECTIVE: To explore the possible significance of aromatase P450 in endometrial hyperplasia with a background of polycystic ovary syndrome (PCOS).
METHODS: Immunohistochemistry was used to determine the expression of aromatase P450 in endometrium of PCOS patients. Semiquantitative analysis of aromatase P450 expression of mRNA and protein level wasalso carried out by real-time quantitative RT-PCR method. After endometrial cells were stimulated by testosterone and letrozole in vitro, the estradiol (E2) level was determined, and the expression of cell aromatase P450 mRNA was assessed.
RESULTS: The aromatase P450 mRNA level was increased in endometria of PCOS patients. When endometrial cells were cultured with 10-6 M testosterone, the E2 level in the culture medium increased. An inhibitory effect on E2 generation and expression of aromatase P450 mRNA was observed when the endometrial cells were treated with 10(-5) M letrozole.
CONCLUSIONS: There is an increased expression of aromatase P450 in PCOS patient endometrium. Androgen stimulation could enhance the synthesis of aromatase P450 mRNA and the production of E2 in endometrial cells in vitro while letrozole could do the reverse.

Liu SX, Xia ZS, Zhong YQ
Gene therapy in pancreatic cancer.
World J Gastroenterol. 2014; 20(37):13343-68 [PubMed] Free Access to Full Article Related Publications
Pancreatic cancer (PC) is a highly lethal disease and notoriously difficult to treat. Only a small proportion of PC patients are eligible for surgical resection, whilst conventional chemoradiotherapy only has a modest effect with substantial toxicity. Gene therapy has become a new widely investigated therapeutic approach for PC. This article reviews the basic rationale, gene delivery methods, therapeutic targets and developments of laboratory research and clinical trials in gene therapy of PC by searching the literature published in English using the PubMed database and analyzing clinical trials registered on the Gene Therapy Clinical Trials Worldwide website (http://www. clinical). Viral vectors are main gene delivery tools in gene therapy of cancer, and especially, oncolytic virus shows brighter prospect due to its tumor-targeting property. Efficient therapeutic targets for gene therapy include tumor suppressor gene p53, mutant oncogene K-ras, anti-angiogenesis gene VEGFR, suicide gene HSK-TK, cytosine deaminase and cytochrome p450, multiple cytokine genes and so on. Combining different targets or combination strategies with traditional chemoradiotherapy may be a more effective approach to improve the efficacy of cancer gene therapy. Cancer gene therapy is not yet applied in clinical practice, but basic and clinical studies have demonstrated its safety and clinical benefits. Gene therapy will be a new and promising field for the treatment of PC.

Smerdová L, Šmerdová J, Kabátková M, et al.
Upregulation of CYP1B1 expression by inflammatory cytokines is mediated by the p38 MAP kinase signal transduction pathway.
Carcinogenesis. 2014; 35(11):2534-43 [PubMed] Related Publications
Cytochrome P450 1B1 (CYP1B1) is an enzyme that has a unique tumor-specific pattern of expression and is capable of bioactivating a wide range of carcinogenic compounds. We have reported previously that coordinated upregulation of CYP1B1 by inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and the aryl hydrocarbon receptor ligands, may increase bioactivation of promutagens, such as benzo[a]pyrene (BaP) in epithelial cells. Here, we extend those studies by describing a novel mechanism participating in the regulation of CYP1B1 expression, which involves activation of the p38 mitogen-activated protein kinase (p38) and mitogen- and stress-activated protein kinase 1 (MSK1). Using inhibitors of p38 and MSKs, as well as mouse embryonic cells derived from p38α-deficient and MSK1/2 double knockout mice, we show here that TNF-α potentiates CYP1B1 upregulation via the p38/MSK1 kinase cascade. Effects of this inflammatory cytokine on CYP1B1 expression further involve the positive transcription elongation factor b (P-TEFb). The inhibition of the P-TEFb subunit, cyclin-dependent kinase 9 (CDK9), which phosphorylates RNA polymerase II (RNAPII), prevented the enhanced CYP1B1 induction by a combination of BaP and inflammatory cytokine. Furthermore, using chromatin immunoprecipitation assays, we found that cotreatment of epithelial cells with TNF-α and BaP resulted in enhanced recruitment of both CDK9 and RNAPII to the Cyp1b1 gene promoter. Overall, these results have implications concerning the contribution of inflammatory factors to carcinogenesis, since enhanced CYP1B1 induction during inflammation may alter metabolism of exogenous carcinogens, as well as endogenous CYP1B1 substrates playing role in tumor development.

Quan L, Hong CC, Zirpoli G, et al.
Variants of estrogen-related genes and breast cancer risk in European and African American women.
Endocr Relat Cancer. 2014; 21(6):853-64 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
It has been observed previously that compared with women of European ancestry (EA), those of African ancestry (AA) are more likely to develop estrogen receptor (ER)-negative breast cancer, although the mechanisms have not been elucidated. We tested the associations between breast cancer risk and a targeted set of 20 genes known to be involved in estrogen synthesis, metabolism, and response and potential gene-environment interactions using data and samples from 1307 EA (658 cases) and 1365 AA (621 cases) participants from the Women's Circle of Health Study (WCHS). Multivariable logistic regression found evidence of associations with single-nucleotide polymorphisms (SNPs) in the ESR1 gene in EA women (rs1801132, odds ratio (OR)=1.47, 95% CI=1.20-1.80, P=0.0002; rs2046210, OR=1.24, 95% CI=1.04-1.47, P=0.02; and rs3020314, OR=1.43, 95% CI=1.19-1.70, P=0.00009), but not in AA women. The only other gene associated with breast cancer risk was CYP1A2 in AA women (rs2470893, OR=1.42, 95% CI=1.00-2.02, P=0.05), but not in EA women. When stratified by ER status, ESR1 rs1801132, rs2046210, and rs3020314 showed stronger associations in ER-positive than in ER-negative breast cancer in only EA women. Associations with the ESR1 SNPs in EA women also appeared to be stronger with longer endogenous estrogen exposure or hormonal replacement therapy use. Our results indicate that there may be differential genetic influences on breast cancer risk in EA compared with AA women and that these differences may be modified by tumor subtype and estrogen exposures. Future studies with a larger sample size may determine the full contribution of estrogen-related genes to racial/ethnic differences in breast cancer.

Yamada T, Okuda Y, Kushida M, et al.
Human hepatocytes support the hypertrophic but not the hyperplastic response to the murine nongenotoxic hepatocarcinogen sodium phenobarbital in an in vivo study using a chimeric mouse with humanized liver.
Toxicol Sci. 2014; 142(1):137-57 [PubMed] Related Publications
High doses of sodium phenobarbital (NaPB), a constitutive androstane receptor (CAR) activator, have been shown to produce hepatocellular tumors in rodents by a mitogenic mode of action (MOA) involving CAR activation. The effect of 1-week dietary treatment with NaPB on liver weight and histopathology, hepatic CYP2B enzyme activity and CYP2B/3A mRNA expression, replicative DNA synthesis and selected genes related to cell proliferation, and functional transcriptomic and metabolomic analyses was studied in male CD-1 mice, Wistar Hannover (WH) rats, and chimeric mice with human hepatocytes. The treatment of chimeric mice with 1000-1500-ppm NaPB resulted in plasma levels around 3-5-fold higher than those observed in human subjects given therapeutic doses of NaPB. NaPB produced dose-dependent increases in hepatic CYP2B activity and CYP2B/3A mRNA levels in all animal models. Integrated functional metabolomic and transcriptomic analyses demonstrated that the responses to NaPB in the human liver were clearly different from those in rodents. Although NaPB produced a dose-dependent increase in hepatocyte replicative DNA synthesis in CD-1 mice and WH rats, no increase in replicative DNA synthesis was observed in human hepatocyte-originated areas of chimeric mice. In addition, treatment with NaPB had no effect on Ki-67, PCNA, GADD45β, and MDM2 mRNA expression in chimeric mice, whereas significant increases were observed in CD-1 mice and/or WH rats. However, increases in hepatocyte replicative DNA synthesis were observed in chimeric mice both in vivo and in vitro after treatment epidermal growth factor. Thus, although NaPB could activate CAR in both rodent and human hepatocytes, NaPB did not increase replicative DNA synthesis in human hepatocytes of chimeric mice, whereas it was mitogenic to rat and mouse hepatocytes. As human hepatocytes are refractory to the mitogenic effects of NaPB, the MOA for NaPB-induced rodent liver tumor formation is thus not relevant for humans.

Bu ZB, Ye M, Cheng Y, Wu WZ
Four polymorphisms in the cytochrome P450 1A2 (CYP1A2) gene and lung cancer risk: a meta-analysis.
Asian Pac J Cancer Prev. 2014; 15(14):5673-9 [PubMed] Related Publications
BACKGROUND: Previous published data on the association between CYP1A2 rs762551, rs2069514, rs2069526, and rs2470890 polymorphisms and lung cancer risk have not allowed a definite conclusion. The present meta-analysis of the literature was performed to derive a more precise estimation of the relationship.
MATERIALS AND METHODS: 8 publications covering 23 studies were selected for this meta-analysis, including 1,665 cases and 2,383 controls for CYP1A2 rs762551 (from 8 studies), 1,456 cases and 1,792 controls for CYP1A2 rs2069514 (from 7 studies), 657 cases and 984 controls for CYP1A2 rs2069526 (from 5 studies) and 691 cases and 968 controls for CYP1A2 rs2470890 (from 3 studies).
RESULTS: When all the eligible studies were pooled into the meta-analysis for the CYP1A2 rs762551 polymorphism, significantly increased lung cancer risk was observed in the dominant model (OR=1.21, 95 % CI=1.00-1.46). In the subgroup analysis by ethnicity, significantly increased risk of lung cancer was observed in Caucasians (dominant model: OR=1.29, 95%CI=1.11-1.51; recessive model: OR=1.33, 95%CI=1.01-1.75; additive model: OR=1.49, 95%CI=1.12-1.98). There was no evidence of significant association between lung cancer risk and CYP1A2 rs2069514, s2470890, and rs2069526 polymorphisms.
CONCLUSIONS: In summary, this meta-analysis indicates that the CYP1A2 rs762551 polymorphism is linked to an increased lung cancer risk in Caucasians. Moreover, our work also points out the importance of new studies for rs2069514 associations in lung cancer, where at least some of the covariates responsible for heterogeneity could be controlled, to obtain a more conclusive understanding about the function of the rs2069514 polymorphism in lung cancer development.

Chu XT, de la Cruz J, Hwang SG, Hong H
Tumorigenic effects of endocrine-disrupting chemicals are alleviated by licorice (Glycyrrhiza glabra) root extract through suppression of AhR expression in mammalian cells.
Asian Pac J Cancer Prev. 2014; 15(12):4809-13 [PubMed] Related Publications
Endocrine-disrupting chemicals (EDCs) have been reported to interfere with estrogen signaling. Exposure to these chemicals decreases the immune response and causes a wide range of diseases in animals and humans. Recently, many studies showed that licorice (Glycyrrhiza glabra) root extract (LRE) commonly called "gamcho" in Korea exhibits antioxidative, chemoprotective, and detoxifying properties. This study aimed to investigate the mechanism of action of LRE and to determine if and how LRE can alleviate the toxicity of EDCs. LRE was prepared by vacuum evaporation and freeze-drying after homogenization of licorice root powder that was soaked in 80% ethanol for 72 h. We used 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as a representative EDC, which is known to induce tumors or cancers; MCF-7 breast cancer cells, used as a tumor model, were treated with TCDD and various concentrations of LRE (0, 50, 100, 200, 400 μg/mL) for 24, 48, and 72 h. As a result, TCDD stimulated MCF-7 cell proliferation, but LRE significantly inhibited TCDD-induced MCF-7 cell proliferation in a dose- and time-dependent manner. The expression of TCDD toxicity-related genes, i.e., aryl hydrocarbon receptor (AhR), AhR nuclear translocator, and cytochrome P450 1A1, was also down-regulated by LRE in a dose-dependent manner. Analysis of cell cycle distribution after treatment of MCF-7 cells with TCDD showed that LRE inhibited the proliferation of MCF-7 cells via G2/M phase arrest. Reverse transcription-polymerase chain reaction and Western blot analysis also revealed that LRE dose-dependently increased the expression of the tumor suppressor genes p53 and p27 and down-regulated the expression of cell cycle-related genes. These data suggest that LRE can mitigate the tumorigenic effects of TCDD in breast cancer cells by suppression of AhR expression and cell cycle arrest. Thus, LRE can be used as a potential toxicity-alleviating agent against EDC-mediated diseases.

Amara I, Touati W, Beaune P, de Waziers I
Mesenchymal stem cells as cellular vehicles for prodrug gene therapy against tumors.
Biochimie. 2014; 105:4-11 [PubMed] Related Publications
Gene-directed enzyme prodrug therapy (GDEPT) consists of targeted delivery to tumor cells of a suicide gene responsible for the in situ conversion of a prodrug into cytotoxic metabolites. One of the major impediments of GDEPT is to target specifically the tumor cells with the suicide gene. Among gene delivery methods, mesenchymal stem cells (MSCs) have emerged recently as potential cellular vehicles for gene delivery. MSCs are particularly suited for gene transduction. They exhibit remarkable migratory property towards tumors and their metastases and they are weakly immunogenic. This review will summarize the current knowledge about MSCs engineered to express different suicide genes (cytosine deaminase, thymidine kinase, carboxylesterase, cytochrome P450) to elicit a significant antitumor response against brain tumors, ovarian, hepatocellular, pancreatic, renal or medullary thyroid carcinomas, breast or prostate cancer and pulmonary metastases. The potential side effects of these MSC-based tumor therapies will also be considered to highlight certain aspects that need to be improved prior to clinical use.

Foulks JM, Carpenter KJ, Luo B, et al.
A small-molecule inhibitor of PIM kinases as a potential treatment for urothelial carcinomas.
Neoplasia. 2014; 16(5):403-12 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
The proto-oncogene proviral integration site for moloney murine leukemia virus (PIM) kinases (PIM-1, PIM-2, and PIM-3) are serine/threonine kinases that are involved in a number of signaling pathways important to cancer cells. PIM kinases act in downstream effector functions as inhibitors of apoptosis and as positive regulators of G1-S phase progression through the cell cycle. PIM kinases are upregulated in multiple cancer indications, including lymphoma, leukemia, multiple myeloma, and prostate, gastric, and head and neck cancers. Overexpression of one or more PIM family members in patient tumors frequently correlates with poor prognosis. The aim of this investigation was to evaluate PIM expression in low- and high-grade urothelial carcinoma and to assess the role PIM function in disease progression and their potential to serve as molecular targets for therapy. One hundred thirty-seven cases of urothelial carcinoma were included in this study of surgical biopsy and resection specimens. High levels of expression of all three PIM family members were observed in both noninvasive and invasive urothelial carcinomas. The second-generation PIM inhibitor, TP-3654, displays submicromolar activity in pharmacodynamic biomarker modulation, cell proliferation studies, and colony formation assays using the UM-UC-3 bladder cancer cell line. TP-3654 displays favorable human ether-à-go-go-related gene and cytochrome P450 inhibition profiles compared with the first-generation PIM inhibitor, SGI-1776, and exhibits oral bioavailability. In vivo xenograft studies using a bladder cancer cell line show that PIM kinase inhibition can reduce tumor growth, suggesting that PIM kinase inhibitors may be active in human urothelial carcinomas.

Kim JS, Roberts JM, Bingman WE, et al.
The prostate cancer TMPRSS2:ERG fusion synergizes with the vitamin D receptor (VDR) to induce CYP24A1 expression-limiting VDR signaling.
Endocrinology. 2014; 155(9):3262-73 [PubMed] Related Publications
A number of preclinical studies have shown that the activation of the vitamin D receptor (VDR) reduces prostate cancer (PCa) cell and tumor growth. The majority of human PCas express a transmembrane protease serine 2 (TMPRSS2):erythroblast transformation-specific (ETS) fusion gene, but most preclinical studies have been performed in PCa models lacking TMPRSS2:ETS in part due to the limited availability of model systems expressing endogenous TMPRSS2:ETS. The level of the active metabolite of vitamin D, 1α,25-dihydroxyvitamin D3 (1,25D), is controlled in part by VDR-dependent induction of cytochrome P450, family 24, subfamily 1, polypeptide1 (CYP24A1), which metabolizes 1,25D to an inactive form. Because ETS factors can cooperate with VDR to induce rat CYP24A1, we tested whether TMPRSS2:ETS would cause aberrant induction of human CYP24A1 limiting the activity of VDR. In TMPRSS2:ETS positive VCaP cells, depletion of TMPRSS2:ETS substantially reduced 1,25D-mediated CYP24A1 induction. Artificial expression of the type VI+72 TMPRSS2:ETS isoform in LNCaP cells synergized with 1,25D to greatly increase CYP24A1 expression. Thus, one of the early effects of TMPRSS2:ETS in prostate cells is likely a reduction in intracellular 1,25D, which may lead to increased proliferation. Next, we tested the net effect of VDR action in TMPRSS2:ETS containing PCa tumors in vivo. Unlike previous animal studies performed on PCa tumors lacking TMPRSS2:ETS, EB1089 (seocalcitol) (a less calcemic analog of 1,25D) did not inhibit the growth of TMPRSS2:ETS containing VCaP tumors in vivo, suggesting that the presence of TMPRSS2:ETS may limit the growth inhibitory actions of VDR. Our findings suggest that patients with TMPRSS2:ETS negative tumors may be more responsive to VDR-mediated growth inhibition and that TMPRSS2:ETS status should be considered in future clinical trials.

Lottrup G, Nielsen JE, Maroun LL, et al.
Expression patterns of DLK1 and INSL3 identify stages of Leydig cell differentiation during normal development and in testicular pathologies, including testicular cancer and Klinefelter syndrome.
Hum Reprod. 2014; 29(8):1637-50 [PubMed] Related Publications
STUDY QUESTION: What is the differentiation stage of human testicular interstitial cells, in particular Leydig cells (LC), within micronodules found in patients with infertility, testicular cancer and Klinefelter syndrome?
SUMMARY ANSWER: The Leydig- and peritubular-cell populations in testes with dysgenesis contain an increased proportion of undifferentiated cells when compared with control samples, as demonstrated by increased delta-like homolog 1 (DLK1) and decreased insulin-like peptide 3 (INSL3) expression.
WHAT IS KNOWN ALREADY: Normal LC function is essential for male development and reproduction. Signs of LC failure, including LC micronodules, are often observed in patients with reproductive disorders.
STUDY DESIGN, SIZE, PARTICIPANTS: In this retrospective study, a panel of markers and factors linked to the differentiation of LCs was investigated in 33 fetal and prepubertal human specimens and in 58 adult testis samples from patients with testicular germ cell tumours, including precursor carcinoma in situ (CIS), infertility or Klinefelter syndrome.
PARTICIPANTS/MATERIALS, SETTING, METHODS: The expression patterns of DLK1, INSL3, chicken ovalbumin upstream promoter transcription factor 2 (COUP-TFII), cytochrome P450, family 11, subfamily A, polypeptide 1 (CYP11A1) and smooth muscle actin (SMA) were investigated by immunohistochemistry and quantitative RT-PCR. The percentage of positive LCs was estimated and correlated to total LC numbers and serum levels of reproductive hormones.
MAIN RESULTS AND THE ROLE OF CHANCE: DLK1, INSL3 and COUP-TFII expression changed during normal development and was linked to different stages of LC differentiation: DLK1 was expressed in all fetal LCs, but only in spindle-shaped progenitor cells and in a small subset of polygonal LCs in the normal adult testis; INSL3 was expressed in a subset of fetal LCs, but in the majority of adult LCs; and COUP-TFII was expressed in peritubular and mesenchymal stroma cells at all ages, in fetal LCs early in gestation and in a subset of adult LCs. CYP11A1 was expressed in the majority of LCs regardless of age and pathology and was the best general LC marker examined here. SMA was weakly expressed in peritubular cells in the fetal and infantile testis, but strongly expressed in the adult testis. In pathological testes, the numbers of DLK1-positive interstitial cells were increased. The proportion of DLK1-positive LCs correlated with total LC numbers (R = 0.53; P < 0.001) and was higher in testis with enlargement of the peritubular layers (P < 0.01), which was also highly associated with DLK1 expression in the peritubular compartment (P < 0.001). INSL3 expression was absent in some, but not all LC micronodules, and in the majority of LCs, it was mutually exclusive of DLK1.
LIMITATIONS, REASONS FOR CAUTION: The number of samples was relatively small and no true normal adult controls were available. True stereology was not used for LC counting, instead LCs were counted in three fields of 0.5 µm(2) surface for each sample.
WIDER IMPLICATIONS OF THE FINDINGS: The population of LCs, especially those clustered in large nodules, are heterogeneous and comprise cells at different stages of differentiation. The study demonstrated that the differentiation and function of LCs, and possibly also peritubular cells, are impaired in adult men with testicular pathologies including testis cancer and Klinefelter syndrome.
STUDY FUNDING/COMPETING INTERESTS: This work was funded by Rigshospitalet's research funds, the Danish Cancer Society and Kirsten and Freddy Johansen's foundation. The authors have no conflicts of interest.

Brinkman AM, Wu J, Ersland K, Xu W
Estrogen receptor α and aryl hydrocarbon receptor independent growth inhibitory effects of aminoflavone in breast cancer cells.
BMC Cancer. 2014; 14:344 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
BACKGROUND: Numerous studies have implicated the aryl hydrocarbon receptor (AhR) as a potential therapeutic target for several human diseases, including estrogen receptor alpha (ERα) positive breast cancer. Aminoflavone (AF), an activator of AhR signaling, is currently undergoing clinical evaluation for the treatment of solid tumors. Of particular interest is the potential treatment of triple negative breast cancers (TNBC), which are typically more aggressive and characterized by poorer outcomes. Here, we examined AF's effects on two TNBC cell lines and the role of AhR signaling in AF sensitivity in these model cell lines.
METHODS: AF sensitivity in MDA-MB-468 and Cal51 was examined using cell counting assays to determine growth inhibition (GI50) values. Luciferase assays and qPCR of AhR target genes cytochrome P450 (CYP) 1A1 and 1B1 were used to confirm AF-mediated AhR signaling. The requirement of endogenous levels of AhR and AhR signaling for AF sensitivity was examined in MDA-MB-468 and Cal51 cells stably harboring inducible shRNA for AhR. The mechanism of AF-mediated growth inhibition was explored using flow cytometry for markers of DNA damage and apoptosis, cell cycle analysis, and β-galactosidase staining for senescence. Luciferase data was analyzed using Student's T test. Three-parameter nonlinear regression was performed for cell counting assays.
RESULTS: Here, we report that ERα-negative TNBC cell lines MDA-MB-468 and Cal51 are sensitive to AF. Further, we presented evidence suggesting that neither endogenous AhR expression levels nor downstream induction of AhR target genes CYP1A1 and CYP1B1 is required for AF-mediated growth inhibition in these cells. Between these two ERα negative cell lines, we showed that the mechanism of AF action differs slightly. Low dose AF mediated DNA damage, S-phase arrest and apoptosis in MDA-MB-468 cells, while it resulted in DNA damage, S-phase arrest and cellular senescence in Cal51 cells.
CONCLUSIONS: Overall, this work provides evidence against the simplified view of AF sensitivity, and suggests that AF could mediate growth inhibitory effects in ERα-positive and negative breast cancer cells, as well as cells with impaired AhR expression and signaling. While AF could have therapeutic effects on broader subtypes of breast cancer, the mechanism of cytotoxicity is complex, and likely, cell line- and tumor-specific.

Efstathiou E, Titus M, Wen S, et al.
Molecular characterization of enzalutamide-treated bone metastatic castration-resistant prostate cancer.
Eur Urol. 2015; 67(1):53-60 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
BACKGROUND: Enzalutamide is a novel antiandrogen with proven efficacy in metastatic castration-resistant prostate cancer (mCRPC).
OBJECTIVE: To evaluate enzalutamide's effects on cancer and on androgens in blood and bone marrow, and associate these with clinical observations.
DESIGN, SETTING, AND PARTICIPANTS: In this prospective phase 2 study, 60 patients with bone mCRPC received enzalutamide 160mg orally daily and had transilial bone marrow biopsies before treatment and at 8 wk of treatment.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Androgen signaling components (androgen receptor [AR], AR splice variant 7 (ARV7), v-ets avian erythroblastosis virus E26 oncogene homolog [ERG], cytochrome P450, family 17, subfamily A, polypeptide 1 [CYP17]) and molecules implicated in mCRPC progression (phospho-Met, phospho-Src, glucocorticoid receptor, Ki67) were assessed by immunohistochemistry; testosterone, cortisol, and androstenedione concentrations were assessed by liquid chromatography-tandem mass spectrometry; AR copy number was assessed by real-time polymerase chain reaction. Descriptive statistics were applied.
RESULTS AND LIMITATIONS: Median time to treatment discontinuation was 22 wk (95% confidence interval, 19.9-29.6). Twenty-two (37%) patients exhibited primary resistance to enzalutamide, discontinuing treatment within 4 mo. Maximal prostate-specific antigen (PSA) decline ≥ 50% and ≥ 90% occurred in 27 (45%) and 13 (22%) patients, respectively. Following 8 wk of treatment, bone marrow and circulating testosterone levels increased. Pretreatment tumor nuclear AR overexpression (> 75%) and CYP17 (> 10%) expression were associated with benefit (p = 0.018). AR subcellular localization shift from the nucleus was confirmed in eight paired samples (with PSA decline) of 23 evaluable paired samples. Presence of an ARV7 variant was associated with primary resistance to enzalutamide (p = 0.018). Limited patient numbers warrant further validation.
CONCLUSIONS: The observed subcellular shift of AR from the nucleus and increased testosterone concentration provide the first evidence in humans that enzalutamide suppresses AR signaling while inducing an adaptive feedback. Persistent androgen signaling in mCRPC was predictive of benefit and ARV7 was associated with primary resistance.
PATIENT SUMMARY: We report a first bone biopsy study in metastatic prostate cancer in humans that searched for predictors of outcome of enzalutamide therapy. Benefit is linked to a pretreatment androgen-signaling signature.
TRIAL REGISTRATION: identifier NCT01091103.

Sharma KL, Rai R, Srivastava A, et al.
A multigenic approach to evaluate genetic variants of PLCE1, LXRs, MMPs, TIMP, and CYP genes in gallbladder cancer predisposition.
Tumour Biol. 2014; 35(9):8597-606 [PubMed] Related Publications
Gallbladder cancer (GBC) is a violent neoplasm associated with late diagnosis, unsatisfactory treatment, and poor prognosis. The disease shows complex interplay between multiple genetic variants. We analyzed 15 polymorphisms in nine genes involved in various pathways to find out combinations of genetic variants contributing to GBC risk. The genes included in the study were matrix metalloproteinases (MMP-2, MMP-7, and MMP-9), tissue inhibitor of metalloproteinases (TIMP-2), cytochrome P450 (CYP)1A1, CYP1B1, phospholipase C epsilon 1 (PLCE1), liver X receptor (LXR)-alpha, and LXR-beta. Genotypes were determined by PCR-RFLP and TaqMan probes. Statistical analysis was done by SPSS version 16. Multilocus analysis was performed by Classification and Regression Tree (CART) analysis and multifactor dimensionality reduction (MDR) to gene-gene interactions in modifying GBC risk. In silico analysis was done using various bioinformatics tools (F-SNP, FAST-SNP). Single locus analysis showed association of MMP-2 (-735 C > T, -1306 C > T), MMP-7 - 181 A > G, MMP-9 (P574R, R668Q), TIMP-2 - 418 G > C, CYP1A1-MspI, CYP1A1-Ile462Val, PLCE1 (rs2274223 A > G, rs7922612 T > C) and LXR-beta T > C (rs3546355 G > A, rs2695121 T > C) polymorphisms with GBC risk (p < 0.05) whereas CYP1B1 and LXR-α variants were not associated with GBC risk. Multidimensional reduction analysis revealed LXR-β (rs3546355 G > A, rs2695121 T > C), MMP-2 (-1306 C > T), MMP-9 (R668Q), and PLCE1 rs2274223 A > G to be key players in GBC causation (p < 0.001, CVC = 7/10). The results were further supported by independent CART analysis (p < 0.001). In silico analysis of associated variants suggested change in splicing or transcriptional regulation. Interactome and STRING analysis showed network of associated genes. The study found PLCE1 and LXR-β network interactions as important contributory factors for genetic predisposition in gallbladder cancer.

Mandić S, Horvat V, Marczi S, et al.
Association study of cytochrome P450 1A1*2A polymorphism with prostate cancer risk and aggressiveness in Croatians.
Coll Antropol. 2014; 38(1):141-6 [PubMed] Related Publications
Cytochrome P450 1A1 (CYP1A1) is an enzyme participating in the bioactivation of various endogenous and environmental reactive compounds that can bind to DNA and thus induce cancerogenesis. Gene encoding the enzyme is expressed in the prostate tissue and is polymorphic. CYP1A1*2A gene polymorphism is associated with elevated enzyme activity and/or inducibility which can lead to accumulation of genotoxic compounds and consequently to cancerogenesis. We examined the association of this polymorphism with prostate cancer (PCa) risk and aggressiveness. The case-control study consisted of 120 PCa patients and 120 benign prostatic hyperplasia (BPH) controls, in Croatian population. Regarding aggressiveness, PCa patients were grouped according to the Gleason score (GS), tumor stage (T) and existence of distant metastasis (M). The polymorphism was analyzed using real-time polymerase chain reaction (PCR). We did not observe association of mutated allele with PCa risk, neither with PCa aggressiveness. Furthermore, frequency of polymorphic genotype was slightly higher in BPH group (16.6% vs. 14.2%, respectively) and also in less aggressive form of PCa (20.4% vs. 9.6% for GS < 7; 15.6% vs. 9.1% for T < 3; 16.7% vs. 10.0% for no distant metastasis). Comparing our findings with other published results, we can assume that the ethnicity influence the genotype distribution and thus may affect the etiology of PCa, even possibly in the way to cause an opposite effect among different ethnic groups. Given the small number of participants, results should be validated on the larger sample size.

Chang BX, You SL, Liu HL, et al.
Establishment of cytochrome P450 3A4 and glutathione S-transferase A1-transfected human hepatoma cell line and functional analysis.
Genet Mol Res. 2014; 13(3):6949-61 [PubMed] Related Publications
This study aimed to enhance the drug metabolism function of the human hepatoma cell line C3A and to explore the related significance for patients with severe liver disease. The important liver phase I and phase II drug metabolism enzymes, cytochrome P450 3A4 (CYP 3A4) and glutathione S-transferase A1 (GST A1), were constructed into a double expression vector and then transfected into C3A cells. Furthermore, in order to increase the expression of CYP 3A4 and GST A1, they were optimized according to human optimal codons. Another double-expression vector, pBudCE4.1-optimized CYP 3A4-optimized GST A1, was constructed and then transfected into C3A to establish a stable cell line. The drug metabolism function of C3A was evaluated. Sequence determination and analysis results showed that the recombinant plasmid pBudCE4.1-CYP 3A4-GST A1 met the application standard and its transfection was successful. The expression and activity of CYP 3A4 and GST A1 in unoptimized C3A cells were higher than those in blank C3A cells. Unoptimized C3A had a better drug metabolism function. Although some C3A cells transfected with pBudCE4.1-optimized CYP 3A4-optimized GST A1 survived, they grew slowly, and were therefore not applicable in clinical practice. Unoptimized C3A is superior to blank C3A in drug metabolism, and could be applied in the bioartificial liver support system as a new material.

Qi DC, Wu B, Tao SL, et al.
Analysis of differentially expressed genes in malignant biliary strictures.
Genet Mol Res. 2014; 13(2):2674-82 [PubMed] Related Publications
Microarray data were collected from bile duct samples from subjects with malignant biliary strictures by endoscopic retrograde cholangiopancreatography to screen for key genes associated with this disease. A predicted interaction network was constructed for these genes to interpret their functions. The gene expression dataset GSE34166 (10 samples: 6 malignant and 4 benign control samples) was downloaded from the Gene Expression Omnibus database. R package scripts were used to process the data and screen for differentially expressed genes. Genes identified were uploaded to the analysis tool String 8.3 to generate a gene interaction network. A hub gene was identified by calculating the node degree. The interaction network of the hub gene with other genes in the human genome was constructed and screened (score >0.9), and pathway-enrichment analysis was performed to elucidate the hub gene function. In total, 377 differentially expressed genes were identified and a network comprising 209 pairs of interactions was constructed. The most critical hub gene was identified as GSTA1, and a GSTA1-based interaction network was constructed consisting of 25 genes (containing the differentially expressed gene GSTA3). The cytochrome P450 (CYP450)-metabolic pathway displayed the most significant enrichment. Additionally, 4 transcription factors and their binding sites were also identified. In conclusion, we have identified the differentially expressed genes GSTA1 (a hub gene) and GSTA3, which may cause abnormal gene expression and tumorigenesis through CYP450-metabolic pathways. The transcription factors and their binding sites in the promoter of the hub gene provide potential directions for future drug design.

Gao W, Liu L, Xu J, et al.
A systematic analysis of predicted MiR-31-targets identifies a diagnostic and prognostic signature for lung cancer.
Biomed Pharmacother. 2014; 68(4):419-27 [PubMed] Related Publications
INTRODUCTION: Recent studies have shown that miR-31 could play a potential role as diagnostic and prognostic biomarkers of several cancers including lung cancer. The aim of this study is to globally summarize the predicting targets of miR-31 and their potential function, pathways and networks, which are involved in the biological behavior of lung cancer.
METHODS: We have conducted the natural language processing (NLP) analysis to identify lung cancer-related molecules in our previous work. In this study, miR-31 targets predicted by combinational computational methods. All target genes were characterized by gene ontology (GO), pathway and network analysis. In addition, miR-31 targets analysis were integrated with the results from NLP analysis, followed by hub genes interaction analysis.
RESULT: We identified 27 hub genes by the final integrative analysis and suggested that miR-31 may be involved in the initiation, progression and treatment response of lung cancer through cell cycle, cytochrome P450 pathway, metabolic pathways, apoptosis, chemokine signaling pathway, MAPK signaling pathway, as well as others.
CONCLUSION: Our data may help researchers to predict the molecular mechanisms of miR-31 in the molecular mechanism of lung cancer comprehensively. Moreover, the present data indicate that the interaction of miR-31 targets may be promising candidates as biomarkers for the diagnosis, prognosis and personalized therapy of lung cancer.

Laws MJ, Kannan A, Pawar S, et al.
Dysregulated estrogen receptor signaling in the hypothalamic-pituitary-ovarian axis leads to ovarian epithelial tumorigenesis in mice.
PLoS Genet. 2014; 10(3):e1004230 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
The etiology of ovarian epithelial cancer is poorly understood, mainly due to the lack of an appropriate experimental model for studying the onset and progression of this disease. We have created a mutant mouse model in which aberrant estrogen receptor alpha (ERα) signaling in the hypothalamic-pituitary-ovarian axis leads to ovarian epithelial tumorigenesis. In these mice, termed ERαd/d, the ERα gene was conditionally deleted in the anterior pituitary, but remained intact in the hypothalamus and the ovary. The loss of negative-feedback regulation by estrogen (E) at the level of the pituitary led to increased production of luteinizing hormone (LH) by this tissue. Hyperstimulation of the ovarian cells by LH resulted in elevated steroidogenesis, producing high circulating levels of steroid hormones, including E. The ERαd/d mice exhibited formation of palpable ovarian epithelial tumors starting at 5 months of age with 100% penetrance. By 15 months of age, 80% of ERαd/d mice die. Besides proliferating epithelial cells, these tumors also contained an expanded population of luteinized stromal cells, which acquire the ability to express P450 aromatase and synthesize E locally. In response to the elevated levels of E, the ERα signaling was accentuated in the ovarian epithelial cells of ERαd/d mice, triggering increased ERα-dependent gene expression, abnormal cell proliferation, and tumorigenesis. Consistent with these findings, treatment of ERαd/d mice with letrozole, an aromatase inhibitor, markedly reduced circulating E and ovarian tumor volume. We have, therefore, developed a unique animal model, which serves as a useful tool for exploring the involvement of E-dependent signaling pathways in ovarian epithelial tumorigenesis.

Xu J, Wang J, Hu Y, et al.
Unequal prognostic potentials of p53 gain-of-function mutations in human cancers associate with drug-metabolizing activity.
Cell Death Dis. 2014; 5:e1108 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
Mutation of p53 is the most common genetic change in human cancer, causing complex effects including not only loss of wild-type function but also gain of novel oncogenic functions (GOF). It is increasingly likely that p53-hotspot mutations may confer different types and magnitudes of GOF, but the evidences are mainly supported by cellular and transgenic animal models. Here we combine large-scale cancer genomic data to characterize the prognostic significance of different p53 mutations in human cancers. Unexpectedly, only mutations on the Arg248 and Arg282 positions displayed significant association with shorter patient survival, but such association was not evident for other hotspot GOF mutations. Gene set enrichment analysis on these mutations revealed higher activity of drug-metabolizing enzymes, including the CYP3A4 cytochrome P450. Ectopic expression of p53 mutant R282W in H1299 and SaOS2 cells significantly upregulated CYP3A4 mRNA and protein levels, and cancer cell lines bearing mortality-associated p53 mutations display higher CYP3A4 expression and resistance to several CYP3A4-metabolized chemotherapeutic drugs. Our results suggest that p53 mutations have unequal GOF activities in human cancers, and future evaluation of p53 as a cancer biomarker should consider which mutation is present in the tumor, rather than having comparison between wild-type and mutant genotypes.

Sundaram K, Sambandam Y, Tsuruga E, et al.
1α,25-dihydroxyvitamin D3 modulates CYP2R1 gene expression in human oral squamous cell carcinoma tumor cells.
Horm Cancer. 2014; 5(2):90-7 [PubMed] Related Publications
Oral squamous cell carcinomas (OSCC) are the most common malignant neoplasms associated with mucosal surfaces of the oral cavity and oropharynx. 1α,25-Dihydroxyvitamin D3 (1,25(OH)2D3) is implicated as an anticancer agent. Cytochrome P450 2R1 (CYP2R1) is a microsomal vitamin D 25-hydroxylase which plays an important role in converting dietary vitamin D to active metabolite, 25-(OH)D3. We identified high levels of CYP2R1 expression using tissue microarray of human OSCC tumor specimens compared to normal adjacent tissue. Therefore, we hypothesize that 1,25(OH)2D3 regulates CYP2R1 gene expression in OSCC tumor cells. Interestingly, real-time RT-PCR analysis of total RNA isolated from OSCC cells (SCC1, SCC11B, and SCC14a) treated with 1,25(OH)2D3 showed a significant increase in CYP2R1 and vitamin D receptor (VDR) mRNA expression. Also, Western blot analysis demonstrated that 1,25(OH)2D3 treatment time-dependently increased CYP2R1 expression in these cells. 1,25(OH)2D3 stimulation of OSCC cells transiently transfected with the hCYP2R1 promoter (-2 kb)-luciferase reporter plasmid demonstrated a 4.3-fold increase in promoter activity. In addition, 1,25(OH)2D3 significantly increased c-Fos, p-c-Jun expression, and c-Jun N-terminal kinase (JNK) activity in these cells. The JNK inhibitor suppresses 1,25(OH)2D3, inducing CYP2R1 mRNA expression and gene promoter activity in OSCC cells. Furthermore, JNK inhibitor significantly decreased 1,25(OH)2D3 inhibition of OSCC tumor cell proliferation. Taken together, our results suggest that AP-1 is a downstream effector of 1,25(OH)2D3 signaling to modulate CYP2R1 gene expression in OSCC tumor cells, and vitamin D analogs could be potential therapeutic agents to control OSCC tumor progression.

Oguro A, Koyama C, Xu J, Imaoka S
A cellular stress response (CSR) that interacts with NADPH-P450 reductase (NPR) is a new regulator of hypoxic response.
Biochem Biophys Res Commun. 2014; 445(1):43-7 [PubMed] Related Publications
NADPH-P450 reductase (NPR) was previously found to contribute to the hypoxic response of cells, but the mechanism was not clarified. In this study, we identified a cellular stress response (CSR) as a new factor interacting with NPR by a yeast two-hybrid system. Overexpression of CSR enhanced the induction of erythropoietin and hypoxia response element (HRE) activity under hypoxia in human hepatocarcinoma cell lines (Hep3B), while knockdown of CSR suppressed them. This new finding regarding the interaction of NPR with CSR provides insight into the function of NPR in hypoxic response.

Wahid M, Mahjabeen I, Baig RM, Kayani MA
Expression of CYP1A1 and GSTP1 in human brain tumor tissues in Pakistan.
Asian Pac J Cancer Prev. 2013; 14(12):7187-91 [PubMed] Related Publications
Most of the exogenous and endogenous chemical compounds are metabolized by enzymes of xenobiotic processing pathways, including the phase I cytochrome p450 species. Carcinogens and their metabolites are generally detoxified by phase II enzymes like glutathione-S-transferases (GST). The balance of enzymes determines whether metabolic activation of pro-carcinogens or inactivation of carcinogens occurs. Under certain conditions, deregulated expression of xenobiotic enzymes may also convert endogenous substrates to metabolites that can facilitate DNA adduct formation and ultimately lead to cancer development. In this study, we aimed to test the association between deregulation of metabolizing genes and brain tumorigenesis. The expression profile of metabolizing genes CYP1A1 and GSTP1 was therefore studied in a cohort of 36 brain tumor patients and controls using Western blotting. In a second part of the study we analyzed protein expression of GSTs in the same study cohort by ELISA. CYP1A1 expression was found to be significantly high (p<0.001) in brain tumor as compared to the normal tissues, with ~4 fold (OR=4, 95%CI=0.43-37) increase in some cases. In contrast, the expression of GSTP1 was found to be significantly low in brain tumor tissues as compared to the controls (p<0.02). This down regulation was significantly higher (OR=0.05, 95%CI=0.006-0.51; p<0.007) in certain grades of lesions. Furthermore, GSTs levels were significantly down-regulated (p<0.014) in brain tumor patients compared to controls. Statistically significant decrease in GST levels was observed in the more advanced lesions (III-IV, p<0.005) as compared to the early tissue grades (I-II). Thus, altered expression of these xenobiotic metabolizing genes may be involved in brain tumor development in Pakistani population. Investigation of expression of these genes may provide information not only for the prediction of individual cancer risk but also for the prevention of cancer.

Dallaglio K, Bruno A, Cantelmo AR, et al.
Paradoxic effects of metformin on endothelial cells and angiogenesis.
Carcinogenesis. 2014; 35(5):1055-66 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
The biguanide metformin is used in type 2 diabetes management and has gained significant attention as a potential cancer preventive agent. Angioprevention represents a mechanism of chemoprevention, yet conflicting data concerning the antiangiogenic action of metformin have emerged. Here, we clarify some of the contradictory effects of metformin on endothelial cells and angiogenesis, using in vitro and in vivo assays combined with transcriptomic and protein array approaches. Metformin inhibits formation of capillary-like networks by endothelial cells; this effect is partially dependent on the energy sensor adenosine-monophosphate-activated protein kinase (AMPK) as shown by small interfering RNA knockdown. Gene expression profiling of human umbilical vein endothelial cells revealed a paradoxical modulation of several angiogenesis-associated genes and proteins by metformin, with short-term induction of vascular endothelial growth factor (VEGF), cyclooxygenase 2 and CXC chemokine receptor 4 at the messenger RNA level and downregulation of ADAMTS1. Antibody array analysis shows an essentially opposite regulation of numerous angiogenesis-associated proteins in endothelial and breast cancer cells including interleukin-8, angiogenin and TIMP-1, as well as selective regulation of angiopioetin-1, -2, endoglin and others. Endothelial cell production of the cytochrome P450 member CYP1B1 is upregulated by tumor cell supernatants in an AMPK-dependent manner, metformin blocks this effect. Metformin inhibits VEGF-dependent activation of extracellular signal-regulated kinase 1/2, and the inhibition of AMPK activity abrogates this event. Metformin hinders angiogenesis in matrigel pellets in vivo, prevents the microvessel density increase observed in obese mice on a high-fat diet, downregulating the number of white adipose tissue endothelial precursor cells. Our data show that metformin has an antiangiogenic activity in vitro and in vivo associated with a contradictory short-term enhancement of pro-angiogenic mediators, as well as with a differential regulation in endothelial and breast cancer cells.

Wang J, Ma D, Li Y, et al.
Targeted delivery of CYP2E1 recombinant adenovirus to malignant melanoma by bone marrow-derived mesenchymal stem cells as vehicles.
Anticancer Drugs. 2014; 25(3):303-14 [PubMed] Related Publications
The aim of this study was to explore the effects of bone marrow-derived mesenchymal stem cells (BMSCs) as intermediate carriers on targeting of P450 gene recombinant adenovirus to malignant melanoma in vitro and in vivo. BMSCs were transduced with pAd5-CMV-CYP2E1 recombinant adenovirus. BMSC migration was detected by Transwell plates in vitro and by superparamagnetic iron oxide particles in vivo. Growth-inhibitory effect and apoptosis were determined by MTT and immunity fluorescence staining. Anticancer effects were examined by a human melanoma nude mouse model in vivo. BMSCs moved toward A375 cells in Transwell plates. Numerous superparamagnetic MSCs labeled with iron oxide were identified in the peripheral areas of the tumor, but were detected in primary organs by Prussian blue staining. BMSC-CYP2E1 cells mediated a bystander killing effect on CYP2E1-negative A375 cells during coculture (IC50 values for A375 cells cocultured with BMSC-EGFP and BMSC-CYP2E1 were 4.08 and 2.68 mmol/l, respectively). Intravenously injecting CYP2E1 recombinant adenovirus-loaded BMSCs in mice with established human melanoma managed to target the tumor site, and BMSCs with forced expression of CYP2E1 inhibited the growth of malignant cells in vivo by activating 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide. BMSCs may serve as a platform of P450 gene-directed enzyme prodrug therapy for the delivery of chemotherapeutic prodrugs to tumors.

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