Gene Summary

Gene:BAX; BCL2 associated X, apoptosis regulator
Aliases: BCL2L4
Summary:The protein encoded by this gene belongs to the BCL2 protein family. BCL2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. This protein forms a heterodimer with BCL2, and functions as an apoptotic activator. This protein is reported to interact with, and increase the opening of, the mitochondrial voltage-dependent anion channel (VDAC), which leads to the loss in membrane potential and the release of cytochrome c. The expression of this gene is regulated by the tumor suppressor P53 and has been shown to be involved in P53-mediated apoptosis. Multiple alternatively spliced transcript variants, which encode different isoforms, have been reported for this gene. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:apoptosis regulator BAX
Source:NCBIAccessed: 30 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 30 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 30 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (9)

Latest Publications: BAX (cancer-related)

Xu F, Song Y, Guo A
Anti-Apoptotic Effects of Docosahexaenoic Acid in IL-1β-Induced Human Chondrosarcoma Cell Death through Involvement of the MAPK Signaling Pathway.
Cytogenet Genome Res. 2019; 158(1):17-24 [PubMed] Related Publications
Osteoarthritis (OA) is a degenerative disease characterized by progressive articular cartilage destruction and joint marginal osteophyte formation with different degrees of synovitis. Docosahexaenoic acid (DHA) is an unsaturated fatty acid with anti-inflammatory, antioxidant, and antiapoptotic functions. In this study, the human chondrosarcoma cell line SW1353 was cultured in vitro, and an OA cell model was constructed with inflammatory factor IL-1β stimulation. After cells were treated with DHA, cell apoptosis was measured. Western blot assay was used to detect protein expression of apoptosis-related factors (Bax, Bcl-2, and cleaved caspase-3) and mitogen-activated protein kinase (MAPK) signaling pathway family members, including extracellular signal-regulated kinase (ERK), c-JUN N-terminal kinase (JNK), and p38 MAPK. Our results show that IL-1β promotes the apoptosis of SW1353 cells, increases the expression of Bax and cleaved caspase-3, and activates the MAPK signaling pathway. In contrast, DHA inhibits the expression of IL-1β, inhibits IL-1β-induced cell apoptosis, and has a certain inhibitory effect on the activation of the MAPK signaling pathway. When the MAPK signaling pathway is inhibited by its inhibitors, the effects of DHA on SW1353 cells are weakened. Thus, DHA enhances the apoptosis of SW1353 cells through the MAPK signaling pathway.

Oronsky B, Scribner C, Aggarwal R, Cabrales P
RRx-001 protects normal tissues but not tumors via Nrf2 induction and Bcl-2 inhibition.
J Cancer Res Clin Oncol. 2019; 145(8):2045-2050 [PubMed] Related Publications
BACKGROUND: RRx-001, a minimally toxic next-generation checkpoint inhibitor that targets myeloid suppressor cells in the tumor microenvironment, has also been shown to protect normal tissues from the cytotoxic effects of chemotherapy and radiation. The following experiments were carried out to determine whether the cytoprotective functions of RRx-001 in normal cells were operative in tumor cells.
DESIGN: The effects of RRx-001 on normal cells, and ovarian cancer A2780 and UWB1 cells were evaluated with a colony-forming assay. Western blot densitometry was used to measure Nrf2 nuclear translocation in Caco2 cells after exposure to RRx-001. Following incubation with RRx-001, levels of the antioxidant, NQO1, were determined in Caco2 cells by measuring absorbance over 300 min at 440 nm. RRx-001-mediated cytotoxicity in HCT-116 colorectal cancer cells was evaluated with an MTT assay. In addition, the effect of RRx-001 incubation on the protein expression of Nrf2, PARP, cleaved PARP, procaspases 3, 8, and 9, Bcl-2, and Bax in HCT-116 colorectal cells was determined by western blot analysis.
RESULTS: RRx-001 is demonstrated to induce Nrf2 in normal tissues, mediating protection, and to downregulate the Nrf2-controlled antiapoptotic target gene, B-cell lymphoma 2 (Bcl-2) in tumors, mediating cytotoxicity.
CONCLUSION: Through Nrf2 induction in normal cells and inhibition of Bcl-2 in tumor cells, RRx-001 selectively protects normal cells against lethality in normal cells, but induces apoptosis in tumor cells.

Qian Z, Yang J, Liu H, et al.
The miR-1204 regulates apoptosis in NSCLC cells by targeting DEK.
Folia Histochem Cytobiol. 2019; 57(2):64-73 [PubMed] Related Publications
INTRODUCTION: This study endeavors to analyze the effects of miR-1204 on the expression of DEK oncogene in non-small cell lung cancer (NSCLC) cell lines and to study the molecular mechanisms of these effects.
MATERIAL AND METHODS: The miR-1204 mimics and inhibitors were transfected into the (A549 and SPC) NSCLC cells. Then the mRNA levels, cell viability, apoptosis rate, morphology and caspase activity were determined. The expression of apoptosis-related proteins Bcl-2 and Bax was also analyzed.
RESULTS: In NSCLC cell lines (A549 and SPC), DEK mRNA levels were down-regulated in miR-1204 overex-pression group. In miR-1204 inhibition group, the expression of DEK mRNA showed an opposite trend. The overexpression of miR-1204 increases the apoptosis rate in NSCLC cells. The Bcl-2 levels in the miR-1204 over-expression group were decreased, while the Bax level was increased. In the miR-1204 inhibition group, expression of Bcl-2 and Bax showed opposite trends. Cell staining revealed cell's morphological changes; the apoptosis in the miR-1204 overexpression group revealed significant morphological features, such as brighter nuclei and nu-clear condensation. Results indicated a typical characteristic of apoptosis in the miR-1204 overexpression group. Caspase-9 and Caspase-3 were involved in the apoptosis pathway, which was mediated by miR-1204 and DEK.
CONCLUSIONS: The miR-1204 induces apoptosis of NSCLC cells by inhibiting the expression of DEK. The mech-anism of apoptosis involves down-regulation of Bcl-2 and up-regulation of Bax expression. Moreover, the apoptosis was mediated by mitochondria-related caspase 9/3 pathway.

El-Shorbagy HM, Eissa SM, Sabet S, El-Ghor AA
Apoptosis and oxidative stress as relevant mechanisms of antitumor activity and genotoxicity of ZnO-NPs alone and in combination with N-acetyl cysteine in tumor-bearing mice.
Int J Nanomedicine. 2019; 14:3911-3928 [PubMed] Free Access to Full Article Related Publications

Mai L, Luo M, Wu JJ, et al.
The combination therapy of HIF1α inhibitor LW6 and cisplatin plays an effective role on anti-tumor function in A549 cells.
Neoplasma. 2019; 2019 [PubMed] Related Publications
Hypoxia-inducible factor 1α (HIF1α) has been demonstrated to be involved in the resistance of various human cancer cells to chemotherapies. However, the correlation between HIF1α and the sensitivity of human non-small cell lung cancer (NSCLC) cells to cisplatin has not been illuminated. The aim of the present study was to investigate the effects of HIF1α on drug resistance in NSCLC cells. A549 cells were incubated in 21% or 0.5% O2 followed by the assessment of the level of HIF1α with qRT-PCR and western blot and ROS level by DCFH-DA assays. Effects of hypoxia or HIF1α inhibitor LW6 on the proliferation and apoptosis of A549 cells were evaluated via CCK-8 and flow cytometry assays. IC50 of A549 cells to cisplatin was determined by MTT assay. The mitochondrial membrane potential (MMP) was measured via JC-1 staining. Moreover, the expression of apoptosis related protein (Bcl-2, Bax) and drug resistance related proteins (MDR1, MRP1) were measured by western blotting. Exposure of A549 cells to 1% O2 significantly up-regulated HIF1α expression, maintained cell viability to cisplatin but decreased the ROS level, which promoted chemoresistance to cisplatin. LW6-treated A549 cells showed an increase in ROS level that blocked the hypoxia induced resistance to cisplatin and in addition, decreased expression of MDR1 and MRP1 in cisplatin-treated cells. This study revealed that hypoxia-improved cisplatin chemoresistance of NSCLC cells by regulated MDR1 and MRP1 expression via HIF1α/ROS pathway is reversed by LW6, suggesting that LW6 may act as effective sensitizer in chemotherapy for NSCLC.

Pradhan N, Parbin S, Kausar C, et al.
Paederia foetida induces anticancer activity by modulating chromatin modification enzymes and altering pro-inflammatory cytokine gene expression in human prostate cancer cells.
Food Chem Toxicol. 2019; 130:161-173 [PubMed] Related Publications
Aberrant epigenetic modifications are responsible for tumor development and cancer progression; however, readily reversible. Bioactive molecules from diets are promising to cure cancer by modulating epigenetic marks and changing immune response. These compounds specifically target the activity of DNMTs and HDACs to cure various human cancers. In view of this, we investigated the anticancer and epigenetic regulatory activities of an edible-plant Paederia foetida. The efficacy of methanolic extract of P. foetida leaves (MEPL) was tested for the modulation of epigenetic factors in gene silencing, i.e. DNMT and HDAC and expression pattern of certain tumor-suppressor genes. After treatment of prostate cancer cells (PC-3 and DU-145) with MEPL, lupeol and β-sitosterol; induction of apoptosis, decrease in cellular-viability and inhibition of cellular-migration were noticed. Simultaneously there was inhibition of DNMT1, HDACs and pro-inflammatory, IL-6, IL1-β, TNF-α and anti-inflammatory, IL-10 genes in cancer and THP1 cell lines. The DNMT1 protein content, enzyme activity and Bcl2 expression decreased significantly; however, expression of E-cadherin (CDH1) and pro-apoptotic gene Bax increased significantly after the treatment of cells with drugs. We conclude plant-derived compounds can be considered to target epigenetic machineries involved with malignant transformation and can open new avenues for cancer therapeutics provoking immune response.

Huang E, Huang H, Guan T, et al.
Involvement of C/EBPβ-related signaling pathway in methamphetamine-induced neuronal autophagy and apoptosis.
Toxicol Lett. 2019; 312:11-21 [PubMed] Related Publications
Methamphetamine (METH) is a widely abused illicit psychoactive drug. Our previous study has shown that CCAAT-enhancer binding protein β (C/EBPβ) is an important regulator in METH-induced neuronal autophagy and apoptosis. However, the detailed molecular mechanisms underlying this process remain poorly understood. Previous studies have demonstrated that DNA damage-inducible transcript 4 (DDIT4), Trib3 (tribbles pseudo kinase 3), alpha-synuclein (α-syn) are involved in METH-induced dopaminergic neurotoxicity. We hypothesized that C/EBPβ is involved in METH-induced DDIT4-mediated neuronal autophagy and Trib3-mediated neuronal apoptosis. We tested our hypothesis by examining the effects of silencing C/EBPβ, DDIT4, Trib3 or α-syn with small interfering ribonucleic acid (siRNA) on METH-induced autophagy and apoptosis in the human neuroblastoma SH-SY5Y cells. We also measured the levels of phosphorylated tuberous sclerosis complex 2 (TSC2) protein and Parkin protein level in SH-SY5Y cells. Furthermore, we demonstrated the effect of silencing C/EBPβ on METH-caused neurotoxicity in the striatum of rats by injecting LV-shC/EBPβ lentivirus using a stereotaxic positioning system. The results showed that METH exposure increased C/EBPβ, DDIT4 protein expression. Elevated DDIT4 expression raised up p-TSC2/TSC2 protein expression ratio, inhibited mTOR signaling pathway, activating cell autophagy. We also found that METH exposure increased the expression of Trib3, α-syn, decreased the Parkin protein expression. Lowering levels of Parkin raised up α-syn expression, which initiated mitochondrial apoptosis by down-regulating anti-apoptotic Bcl-2, followed by up-regulation of pro-apoptotic Bax, resulting in translocation of cytochrome c (cyto c), an apoptogenic factor, from the mitochondria to cytoplasm and activation of caspase-dependent pathways. These findings were supported by data showing METH-induced autophagy and apoptosis was significantly inhibited by silencing C/EBPβ, DDIT4, Trib3 or α-syn, or by Parkin over-expression. Based on the present data, a novel of mechanism on METH-induced cell toxicity is proposed, METH exposure increased C/EBPβ protein expression, triggered DDIT4/TSC2/mTOR signaling pathway, and evoked Trib3/Parkin/α-syn-related mitochondrial apoptotic signaling pathway. Collectively, these results suggest that C/EBPβ plays an important role in METH-triggered autophagy and apoptosis and it may be a potential target for therapeutics in METH-caused neurotoxicity.

Chen B, Shen Z, Wu D, et al.
Glutathione Peroxidase 1 Promotes NSCLC Resistance to Cisplatin via ROS-Induced Activation of PI3K/AKT Pathway.
Biomed Res Int. 2019; 2019:7640547 [PubMed] Free Access to Full Article Related Publications
Purpose: Reactive oxygen species (ROS)-induced cytotoxicity is an important mechanism by which cisplatin kills tumor cells. Glutathione peroxidase family (GPXs) is an important member of antioxidant system which metabolizes intracellular ROS and maintains homeostasis of cells. Altered expressions of GPXs enzymes, especially GPX1, have been described in a variety of human cancers. However, their functional roles in cisplatin-based chemoresistance in human malignancies including non-small cell lung cancer have never been explored.
Methods: A panel of NSCLC cell lines were selected for this study. GPX1 expression was detected using quantitative RT-PCR and Western blot. Cisplatin-induced cell killing was analyzed by CCK8 assay. Intracellular ROS levels were detected by fluorescence-based flow cytometry analysis. In vitro overexpression and knockdown of GPX1 expression were performed using GPX1 expression vector and siRNA approaches. Protein levels of PTEN, NF-
Results: GPX1 expression was upregulated in a subset of NSCLC cell lines resistant to cisplatin treatment. Expression vector-mediated forced overexpression of GPX1 significantly increased cisplatin resistance in NSCLC cell lines, whereas RNA inference-mediated downregulation of GPX1 could restore sensitivity to cisplatin. Overexpression of GPX1 significantly suppressed elevation of intracellular ROS and activation of AKT pathway when NSCLC cell lines were exposed to different concentrations of cisplatin. Activation of the AKT pathway inhibited proapoptotic cascade and subsequently led to cisplatin resistance in NSCLC cells. Inhibition of NF-
Conclusions: Our findings suggested that overexpression of GPX1 is a novel molecular mechanism for cisplatin-based chemoresistance in NSCLC. GPX1 overexpression blocks cisplatin-induced ROS intracellular accumulation, activates PI3K-AKT pathway by increased AKT phosphorylation, and further leads to cisplatin resistance in NSCLC cells. Inhibition of NF-

Ameri Z, Ghiasi S, Farsinejad A, et al.
Telomerase inhibitor MST-312 induces apoptosis of multiple myeloma cells and down-regulation of anti-apoptotic, proliferative and inflammatory genes.
Life Sci. 2019; 228:66-71 [PubMed] Related Publications
AIMS: The telomerase-based therapy of cancer has received a great deal of attention due to the fact that it is expressed in almost all of the cancer cells while it is inactivated in most of the normal somatic cells. Current investigation was aimed to examine the effects of namely telomerase inhibitor, the MST-312, as a chemically modified derivative of epigallocatechin gallate (EGCG), on human multiple myeloma cell line U-266.
MAIN METHODS: U-266 cells were cultured and then treated by MST-312. The viability of cultured cells was measured by both trypan blue staining and MTT assay techniques. To examine the apoptosis, annexin-V/7-AAD staining using flow cytometry method was employed. To analysis the expression of Bax, Bcl-2, c-Myc, hTERT, IL-6 and TNF-α genes, the quantitative real-time PCR was employed.
KEY FINDINGS: We observed the short-term dose-dependent cytotoxic and apoptotic effect of MST-312 against U-266 myeloma cells. Gene expression analysis indicated that the MST-312-based apoptosis was associated with up-regulation of pro-apoptotic gene (Bax) as well as down-regulation of anti-apoptotic (Bcl-2), proliferative (c-Myc, hTERT) and inflammatory (IL-6, TNF-α) genes.
SIGNIFICANCE: These findings suggest that telomerase-based therapy using MST-312 may represent a novel promising strategy for treatment of multiple myeloma.

Cirmi S, Ferlazzo N, Gugliandolo A, et al.
Moringin from
Int J Mol Sci. 2019; 20(8) [PubMed] Free Access to Full Article Related Publications
In the last decades, glucosinolates (GLs), precursors of isothiocyanates (ITCs), have been studied mostly for their chemopreventive and chemotherapeutic properties. The aim of our research was to study the antiproliferative effect of 4-(α-L-rhamnopyranosyloxy) benzyl glucosinolate (glucomoringin; GMG) bioactivated by myrosinase enzyme to form the corresponding isothiocyanate 4-(α-L-rhamnopyranosyloxy) benzyl C (moringin) in SH-SY5Y human neuroblastoma cells. We found that moringin significantly reduced SH-SY5Y cell growth in a time and concentration-dependent (

Li Y, Pan J, Gou M
The Anti-Proliferation, Cycle Arrest and Apoptotic Inducing Activity of Peperomin E on Prostate Cancer PC-3 Cell Line.
Molecules. 2019; 24(8) [PubMed] Free Access to Full Article Related Publications
Peperomin E is a natural secolignan existing distributed in the plants of the genus

Kubatka P, Uramova S, Kello M, et al.
Anticancer Activities of
Int J Mol Sci. 2019; 20(7) [PubMed] Free Access to Full Article Related Publications
Naturally-occurring mixtures of phytochemicals present in plant foods are proposed to possess tumor-suppressive activities. In this work, we aimed to evaluate the antitumor effects of

Zhang Q, Di C, Yan J, et al.
Inhibition of SF3b1 by pladienolide B evokes cycle arrest, apoptosis induction and p73 splicing in human cervical carcinoma cells.
Artif Cells Nanomed Biotechnol. 2019; 47(1):1273-1280 [PubMed] Related Publications
Pladienolide B is a potent cancer cell growth inhibitor that targets the SF3b1 subunit of the spliceosome. There is considerable interest in the compound as a tool to study SF3b1 function in cancer. However, so far little information is available on the molecular mechanism of SF3b1 eliciting apoptosis in cancer cells. Here, we investigated the molecular mechanism of SF3b1 eliciting apoptosis in human cervical carcinoma cells. We demonstrated that inhibition of SF3b1 by pladienolide B inhibited proliferation of HeLa cells at low nanomolar concentrations in a dose- and time-dependent manner. It also induced G2/M phase arrest and significant rise of apoptotic cells. Moreover, it is indicated that inhibition of SF3b1 by pladienolide B induced Tap73/ΔNp73 expression and consequently down-regulated Bax/Bcl-2 ratio, cytochrome c release and caspase-3 expression. Thus, our results showed that SF3b1 plays a pivotal role in cycle arrest, apoptosis induction, and p73 splicing in human cervical carcinoma cells, suggesting that SF3b1 could be used as a potential candidate for cervical cancer therapy.

Rahimi Kalateh Shah Mohammad G, Seyedi SMR, Karimi E, Homayouni-Tabrizi M
The cytotoxic properties of zinc oxide nanoparticles on the rat liver and spleen, and its anticancer impacts on human liver cancer cell lines.
J Biochem Mol Toxicol. 2019; 33(7):e22324 [PubMed] Related Publications
INTRODUCTION: Due to their unique properties including cellular uptake and the delivery efficiency to biological systems, nanoparticles are used in various preclinical and clinical applications. The aim of this study was to investigate the toxicity impacts of zinc oxide nanoparticles (ZnO-NPs) on morphology and functionality of the rat's liver and spleen and illustrated its safe-therapeutic doses.
METHODS: The 28 female Swiss albino rats (180-220 g) and two human hepatocyte cell lines (HepG2 and HUH7) were designed as an in vivo and in vitro study, respectively. Samples were treated with certain doses of ZnO-NPs. The rat's liver morphology and functionality and apoptotic genes expression profile (Bax, Bcl-2, and P53) were analyzed to detect the cytotoxicity and antitumor impacts of ZnO-NPs, respectively.
RESULTS: The results showed a positive significant association between the increasing doses of ZnO-NPs and alanine aminotransferase/aspartate aminotransferase values. Moreover, a meaningful correlation was detected between the rat's liver and spleen weight and ZnO-NPs doses. Furthermore, the histopathological analysis of rat's liver showed the individual cytotoxic properties of ZnO-NPs. Finally, the positive significant correlation was detected among the expression of Bax and P53 genes with ZnO-NPs. In addition, the negative correlation was demonstrated between the expression of Bcl-2 and ZnO-NPs.
CONCLUSION: In general, in the current study, the antitumor effects of ZnO-NPs were confirmed by the enhancement of P53 and Bax genes expression profile, which are indicated the apoptotic induction in HUH7 cell line. Moreover, we introduced a safe-clinical ZnO-NPs dosage, have antitumor effects.

Li D, Zhang T, Lai J, et al.
MicroRNA‑25/ATXN3 interaction regulates human colon cancer cell growth and migration.
Mol Med Rep. 2019; 19(5):4213-4221 [PubMed] Free Access to Full Article Related Publications
The present study aimed to investigate the function of microRNA‑25 (miR‑25) in human colon cancer cell viability and migration in addition to the underlying possible mechanisms. miR‑25 expression was upregulated in patients with colon cancer compared with the control group. Reverse transcription‑quantitative polymerase chain reaction and gene chip technology were used to analyze the alterations of miR‑25 in patients with colon cancer. Cell viability and cell migration were analyzed using MTT and wound healing assays, respectively, apoptosis was analyzed using flow cytometry, and western blot analysis was conducted to determine the protein expression of ataxin‑3 (ATXN3), apoptosis regulator Bax (Bax) and cyclin D1. Overexpression of miR‑25 increased cell viability and migration, decreased apoptosis, decreased caspase‑3/9 activity level in addition to decreased Bax protein expression, and increased cyclin D1 protein expression in colon cancer cells. Furthermore, miR‑25 was demonstrated to target ATXN3 and suppress ATXN3 protein expression. Downregulation of miR‑25 induced apoptosis of colon cancer cells via increased expression ATXN3. Small interfering‑ATXN3 inhibited the anti‑cancer effects of miR‑25 downregulation in colon cancer. Collectively, the present results demonstrated that miR‑25 promoted human colon cancer cell viability and migration by regulating ATXN3 expression.

Velinovic M, Jankovic R, Jovanovic D, et al.
Tumor characteristics, expressions of ERCC1, Bax, p53, IGF1R, Bcl2, Bcl2/Bax and prognostic factors for overall survival in patients with lung carcinoid.
J BUON. 2019 Jan-Feb; 24(1):256-266 [PubMed] Related Publications
PURPOSE: Neuroendocrine lung tumors (NET) include typical carcinoids (TC), atypical carcinoids (AC), large cell NE carcinoma (LCNEC) and small-cell carcinoma (SCLC), with different clinicopathological profiles and relative grades of malignancy. Although differences between carcinoids and high grade carcinomas are recognized, precise differences and behavior of TC and AC have not been clearly defined. The aim of this study was to better define the differences in the clinical behavior of TC and AC, and to establish new prognostic factors of overall survival (OS), by determining the levels of genetic expression of IGF1R, ERCC1, Bax, p53, Bcl2 and Bcl2/Bax ratio.
METHODS: The histopathological diagnosis of 52 surgically resected pulmonary carcinoid tumors was made according to the WHO classification. Gene expressions were evaluated by quantitative real-time PCR.
RESULTS: The confirmed prognostic factors for overall survival (OS) were pTNM T (p<0.01), pTNM N (p<0.05), clinical stage (p<0.05), type of surgery (p<0.01) and histopathological (HP) tumor type (p<0.05). Bcl2 mRNA level and Bcl2/Bax ratio were found to have a potential for discrimination of the HP type of tumor (AC vs TC, Receiver Operating Characteristics (ROC) cut-off values 0.1451 and 0.3015, respectively), but without statistically significant impact on OS.
CONCLUSIONS: In patients with NETs, smaller primary tumor, absence of positive lymph nodes, and TC type of tumor predicted longer OS. Type of resection has influence on OS. Bcl2 expression and Bcl2/Bax ratio might be valuable as independent diagnostic parametars in lung carcinoids. Therapeutic approaches using attenuation of Bcl2 or upregulation of Bax might prove useful in lung NETs.

Jeong Y, Lim JW, Kim H
Lycopene Inhibits Reactive Oxygen Species-Mediated NF-κB Signaling and Induces Apoptosis in Pancreatic Cancer Cells.
Nutrients. 2019; 11(4) [PubMed] Free Access to Full Article Related Publications
Generation of excess quantities of reactive oxygen species (ROS) caused by mitochondrial dysfunction facilitates rapid growth of pancreatic cancer cells. Elevated ROS levels in cancer cells cause an anti-apoptotic effect by activating survival signaling pathways, such as NF-κB and its target gene expression. Lycopene, a carotenoid found in tomatoes and a potent antioxidant, displays a protective effect against pancreatic cancer. The present study was designed to determine if lycopene induces apoptosis of pancreatic cancer PANC-1 cells by decreasing intracellular and mitochondrial ROS levels, and consequently suppressing NF-κB activation and expression of NF-κB target genes including cIAP1, cIAP2, and survivin. The results show that the lycopene decreased intracellular and mitochondrial ROS levels, mitochondrial function (determined by the mitochondrial membrane potential and oxygen consumption rate), NF-κB activity, and expression of NF-κB-dependent survival genes in PANC-1 cells. Lycopene reduced cell viability with increases in active caspase-3 and the Bax to Bcl-2 ratio in PANC-1 cells. These findings suggest that supplementation of lycopene could potentially reduce the incidence of pancreatic cancer.

Gong P, Wang Y, Jing Y
Apoptosis Induction byHistone Deacetylase Inhibitors in Cancer Cells: Role of Ku70.
Int J Mol Sci. 2019; 20(7) [PubMed] Free Access to Full Article Related Publications
Histone deacetylases (HDACs) are a group of enzymes that regulate gene transcription by controlling deacetylation of histones and non-histone proteins. Overexpression of HDACs is found in some types of tumors and predicts poor prognosis. Five HDAC inhibitors are approved for the treatment of cutaneous T-cell lymphoma, peripheral T-cell lymphoma, and multiple myeloma. Treatment with HDAC inhibitors regulates gene expression with increased acetylated histones with unconfirmed connection with therapy. Apoptosis is a key mechanism by which HDAC inhibitors selectively kill cancer cells, probably due to acetylation of non-histone proteins. Ku70 is a protein that repairs DNA breaks and stabilizes anti-apoptotic protein c-FLIP and proapoptotic protein Bax, which is regulated by acetylation. HDAC inhibitors induce Ku70 acetylation with repressed c-FLIP and activated Bax in cancer cells. Current studies indicate that Ku70 is a potential target of HDAC inhibitors and plays an important role during the induction of apoptosis.

Son Y, An Y, Jung J, et al.
Protopine isolated from Nandina domestica induces apoptosis and autophagy in colon cancer cells by stabilizing p53.
Phytother Res. 2019; 33(6):1689-1696 [PubMed] Related Publications
The tumor suppressor p53 plays essential roles in cellular protection mechanisms against a variety of stress stimuli and its activation induces apoptosis or autophagy in certain cancer cells. Here, we identified protopine, an isoquinoline alkaloid isolated from Nandina domestica, as an activator of the p53 pathway from cell-based natural compound screening based on p53-responsive transcription. Protopine increased the p53-mediated transcriptional activity and promoted p53 phosphorylation at the Ser15 residue, resulting in stabilization of p53 protein. Moreover, protopine up-regulated the expression of p21

Cai MJ, Cui Y, Fang M, et al.
Inhibition of PSMD4 blocks the tumorigenesis of hepatocellular carcinoma.
Gene. 2019; 702:66-74 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver with high mortality and frequent recurrence. Although various therapies provide potential cure for HCC patients, unfortunately the five-year survival rate of advanced HCC remains dismal. It is critical to explore the pathogenesis of HCC and identify novel biomarkers for early HCC diagnosis. PSMD4 is a major receptor of the 26S proteasome involved in ubiquitindependent and proteasome-mediated protein degradation. In our study, PSMD4 was overexpressed in HCC tissues and cell lines determined by Northern blot, western blot and immunohistochemistry. The silencing of PSMD4 blocked cell proliferation and tumor growth, induced cell apoptosis and inhibited the proteasome activity. Western blot results showed that the knockdown of PSMD4 blocked the expression of cyclooxygenase 2 (COX2), phosphorylated Sarcoma tyrosine kinase (P-SRC) and Bcl-2, but improved the levels of p53 and Bax in HCC, lung cancer, colorectal cancer, breast cancer and endometrial cancer cell lines. Taken together, these findings indicated that the subunit of 26S proteasome PSMD4 exerts as an oncogene in HCC and other cancers via regulating the expression p53, Bcl-2 and Bax. These findings enriched the pathogenesis of HCC, and provided a new biomarker for cancers diagnosis and a new target for cancers therapy.

Hu F, He Z, Sun C, Rong D
Knockdown of GRHL2 inhibited proliferation and induced apoptosis of colorectal cancer by suppressing the PI3K/Akt pathway.
Gene. 2019; 700:96-104 [PubMed] Related Publications
Grainyhead-like 2 (GRHL2) transcription factor is implicated in many types of cancers. However, the role of GRHL2 in colorectal cancer (CRC) has not been fully understood. The present study aimed to evaluate the expression and functional roles of GRHL2 in CRC. The expression of GRHL2 in normal human intestinal epithelial cells and colorectal cancer cells was measured by qRT-PCR and western blot. For knockdown of GRHL2, two small interfere RNAs (siRNAs) targeting GRHL2 or control siRNA was transfected into CRC cell lines (HCT116 and HT29). For GRHL2 overexpression, the GRHL2-overexpressing vector or empty lentiviral vector was infected into HCT116 and HT29 cells. Cell proliferation was measured by MTT assay. Cell apoptosis rate was analyzed by flow cytometry. The expression of proliferating cell nuclear antigen (PCNA), Bax, and Bcl-2 was detected by western blot. We found that GRHL2 was upregulated in CRC cells compared to normal human intestinal epithelial cells. Knockdown of GRHL2 inactivated the PI3K/Akt pathway in HCT116 and HT29 cells. Knockdown of GRHL2 inhibited cell viability, elevated the apoptosis rates, suppressed the expression of PCNA and Bcl-2, and induced the expression of Bax in HCT116 and HT29 cells, and these effects were reversed by activation of the PI3K/Akt pathway. Inhibition of PI3K/Akt pathway blocked the effects of GRHL2 overexpression on cell proliferation and apoptosis. In conclusion, GRHL2 acted as an oncoprotein through regulating cell proliferation and apoptosis in CRC cells. The PI3K/Akt pathway was closely involved in the effects of GRHL2. Therefore, GRHL2 might be a therapeutic target for the CRC treatment.

Rutz J, Maxeiner S, Juengel E, et al.
Growth and Proliferation of Renal Cell Carcinoma Cells Is Blocked by Low Curcumin Concentrations Combined with Visible Light Irradiation.
Int J Mol Sci. 2019; 20(6) [PubMed] Free Access to Full Article Related Publications
The anti-cancer properties of curcumin in vitro have been documented. However, its clinical use is limited due to rapid metabolization. Since irradiation of curcumin has been found to increase its anti-cancer effect on several tumor types, this investigation was designed to determine whether irradiation with visible light may enhance the anti-tumor effects of low-dosed curcumin on renal cell carcinoma (RCC) cell growth and proliferation. A498, Caki1, and KTCTL-26 cells were incubated with curcumin (0.1⁻0.4 µg/mL) and irradiated with 1.65 J/cm² visible light for 5 min. Controls were exposed to curcumin or light alone or remained untreated. Curcumin plus light, but not curcumin or light exposure alone altered growth, proliferation, and apoptosis of all three RCC tumor cell lines. Cells were arrested in the G0/G1 phase of the cell cycle. Phosphorylated (p) CDK1 and pCDK2, along with their counter-receptors Cyclin B and A decreased, whereas p27 increased. Akt-mTOR-signaling was suppressed, the pro-apoptotic protein Bcl-2 became elevated, and the anti-apoptotic protein Bax diminished. H3 acetylation was elevated when cells were treated with curcumin plus light, pointing to an epigenetic mechanism. The present findings substantiate the potential of combining low curcumin concentrations and light as a new therapeutic concept to increase the efficacy of curcumin in RCC.

Li XF, Zhao GQ, Li LY
Ginsenoside impedes proliferation and induces apoptosis of human osteosarcoma cells by down-regulating β-catenin.
Cancer Biomark. 2019; 24(4):395-404 [PubMed] Related Publications
BACKGROUND: Osteosarcoma (OS) is the most commonly occurred primary bone malignancy with high incident rates among children and adolescents. In pharmacologic treatment, the drug ginsenoside has been shown to exert anticancer effects on several malignant diseases. The purpose of this research was to investigate the effect of ginsenoside on the apoptosis and proliferation of human OS MG-63 and Saos-2 cells by regulating the expression of β-catenin.
METHODS: Human OS MG-63 and Saos-2 cells were assigned into control group, and four groups with treatment by varying concentrations (12.5 μg/mL, 25 μg/mL, 50 μg/mL and 100 μg/mL) of ginsenoside, respectively. Cell growth after treatment was observed through cell slides. The proliferation rate of MG-63 and Saos-2 cells in each group was detected by CCK-8. After cell transfection at 48 h, cell cycle and cell apoptosis were detected by FITC-Annexin V staining and flow cytometry. The protein and mRNA expressions of β-catenin, Cyclin D1, Bcl-2, Bax and cleaved caspase-3 were detected by RT-qPCR and western blot analysis.
RESULTS: With increased exposure and concentration of ginsenoside, the cell density, total cell numbers and the absorbance of MG-63 and Saos-2 cells gradually decreased. FITC-Annexin V and FITC-Annexin V/PI staining demonstrated that the cell proportion at S phase decreased, whereas the total apoptotic rate of MG-63 and Saos-2 cells was increased. Furthermore, RT-qPCR and western blot analysis highlighted a gradual decrease in protein and mRNA expressions of β-catenin, Bcl-2 and Cyclin D1, while an elevation in those of Bax and cleaved caspase-3.
CONCLUSION: The results of this study demonstrate that ginsenoside inhibits proliferation and promotes apoptosis of human OS MG-63 and Saos-2 cells by reducing the expressions of β-catenin, Bcl-2 and Cyclin D1 and increasing the expression of Bax and cleaved caspase-3.

Jia Y, Lin R, Jin H, et al.
MicroRNA-34 suppresses proliferation of human ovarian cancer cells by triggering autophagy and apoptosis and inhibits cell invasion by targeting Notch 1.
Biochimie. 2019; 160:193-199 [PubMed] Related Publications
Ovarian cancer is one the prevalent cancers in women and is responsible for 5% of all the cancer related mortalities in women. Owing to late diagnosis, frequent relapses, side effects of chemotherapy, development of drug resistance, there is pressing need to screen out novel and effective treatment options. Accumulating evidences suggest that miRNAs may prove essential therapeutic targets for the treatment of cancer. This study was designed to investigate the role and therapeutic potential of miR-34 in ovarian cancer. It was found that miR-34 is significantly downregulated in ovarian cancer cell lines. Overexpression of miR-34 causes significant decrease in the proliferation of OVACAR-3 ovarian cancer cells via activation of apoptosis and autophagy. The miR-34 overexpression was concomitant with upsurge of apoptosis related proteins (Bax) and the autophagy associated protein (LC3 II and p62). TargetScan analysis showed Notch 1 to be the main target of miR-34 in OVACAR-3 cells which was further validated by luciferase reporter assay. The qRT-PCR results showed Notch 1 to be 3.2-4.1 fold higher in the ovarian cancer cell lines relative to the non-cancerous cells. Nonetheless, miR-34 overexpression in OVACAR-3 cells resulted in the post-transcriptional suppression of Notch 1 expression. Silencing of Notch 1 also caused inhibition of OVACAR-3 cell proliferation via induction of apoptosis and autophagy. Overexpression of Notch 1 could partially rescue the effects of miR-34 overexpression on the proliferation of OVACAR-3 cells. Moreover, overexpression of miR-34 causes significant inhibition of the invasion of the OVACAR-3 cells. The findings of the present study indicate the tumor suppressive role of miR-34 in ovarian cancer and may therefore prove to be a potential therapeutic target.

Zhang H, Dong R, Zhang P, Wang Y
Songorine suppresses cell growth and metastasis in epithelial ovarian cancer via the Bcl‑2/Bax and GSK3β/β‑catenin signaling pathways.
Oncol Rep. 2019; 41(5):3069-3079 [PubMed] Related Publications
Epithelial ovarian cancer (EOC) is the most frequent cause of cancer‑associated mortality among all types of gynecological cancer. The high recurrence rate and the poor 5‑year survival rate indicate that more effective therapeutic strategies are required. The aim of the present study was to investigate the role and potential mechanisms of songorine in treating EOC. EOC cells were cultured with different concentrations of songorine, following which MTT and flow cytometric analyses were conducted to measure cell viability and apoptosis. Wound healing and Transwell assays were used to detect cell migration and invasion abilities. Furthermore, associated molecules in the glycogen synthase kinase (GSK)‑3β/β‑catenin and B‑cell lymphoma 2 (Bcl‑2)/Bcl‑2‑associated X (Bax) signaling pathways were semi‑quantified by western blotting. Finally, tumor size measurements, pathological observations, western blot analysis and toxicological evaluations were performed in SKOV‑3 tumor‑bearing BALB/c nude mice to investigate the efficacy and safety of songorine. As expected, songorine inhibited EOC cell survival, invasion and migration, promoted EOC cell apoptosis and suppressed mammalian EOC tumorigenic behavior. In particular, GSK3β inhibitor treatment restored the songorine‑induced regulation of the GSK3β/β‑catenin signaling pathway. Furthermore, in the in vitro and in vivo experiments, songorine consistently downregulated the expression of N‑cadherin, vimentin, matrix metalloproteinase (MMP)‑2, MMP‑9, phosphorylated‑GSK3β, β‑catenin and Bcl‑2, and upregulated the expression of E‑cadherin, cleaved caspase‑3, cleaved caspase‑9 and Bax. In conclusion, songorine exerted its anticancer effect through the GSK3β/β‑catenin and Bcl‑2/Bax signaling pathways. These results highlight the potential use of songorine as a novel therapeutic agent for EOC.

Quan M, Liu S, Zhou L, et al.
Hepatitis C virus nonstructural 5A protein inhibits the starvation‑induced apoptosis of hepatoblastoma cells by increasing Beclin 1 expression.
Oncol Rep. 2019; 41(5):3051-3059 [PubMed] Related Publications
Hepatitis C virus (HCV) nonstructural protein 5A (NS5A) modulates cellular apoptosis, which is involved in the occurrence and development of liver cancer. The mechanisms of apoptosis inhibition by NS5A in liver cancer cells remains unclear. Beclin 1, which functions upstream of autophagosome formation, is upregulated by NS5A. Autophagy, an evolutionarily conserved catabolic process, has a crucial role in tumor initiation and progression. Autophagy was blocked by inhibitors 3‑methyladenine and chloroquine, or via knockdown of Beclin 1. Flow cytometric analysis and western blotting were used to detect apoptosis. It was found that inhibition of autophagy attenuated the NS5A‑mediated apoptosis inhibition of HepG2 cells. Furthermore, it was confirmed that Beclin 1 expression by NS5A was involved in the negative regulation of starvation‑induced liver cancer apoptosis, which was accompanied by reduced p53 and apoptosis regulator Bax expression, as well as decreased caspase‑3/-7 activation. Therefore, inhibition of autophagy may be promising therapeutic strategy in the treatment of HCV‑associated liver cancer.

Shakibaie M, Vaezjalali M, Rafii-Tabar H, Sasanpour P
Synergistic effect of phototherapy and chemotherapy on bladder cancer cells.
J Photochem Photobiol B. 2019; 193:148-154 [PubMed] Related Publications
Drug resistance as an important barrier to cancer treatment, has a close relation with alteration of cancer metabolism. Therefore, in this study the synergistic effect of phototherapy and chemotherapy were investigated on the bladder cancer cells viability. The cytotoxicity effect of blue light irradiation was measured by the MTT assay. Glucose consumption, lactate and ammonium formation were analyzed in the blue LED-irradiated cancer cells culture. Also, the expression of some genes involved in apoptosis and epithelial-mesenchymal transition was assessed using real-time PCR in comparison with the control group. The analysis of the results indicated that blue light irradiation inhibited the cell viability in a dose-dependent manner. Blue light irradiation decreased the cell viability by 7% and 19% (p < .05) in 5637 cells at doses of 8.7 J/cm

Alem M, Shahbazfar AA, Zare P, Tayefi-Nasrabadi H
The effects of coadministration of tilorone dihydrochloride and culture supernatants from
J Cancer Res Ther. 2019 Jan-Mar; 15(1):176-184 [PubMed] Related Publications
Context: Tilorone dihydrochloride is a therapeutic agent with a different mechanism in cancer. The species of Lactobacillus have an important role in cytotoxic effect.
Aims: Because of unknown effects of tilorone and culture supernatants from Lactobacillus reuteri on hepatoma, the aim of this study is to evaluate apoptotic, cytotoxic, and therapeutic effects of tilorone on mouse hepatoma cell line with and without culture supernatants from L. reuteri.
Materials and Methods: To do so, after cell line culture, cells were divided into different groups such as negative control, treatment with four doses of tilorone, positive control of supernatant (single dose), and combination therapy groups of different doses of tilorone with supernatant (constant doses), for 48 h. All groups were studied with pathologic tests, biochemical study, tetrazolium dye (3-(4, 5- dimethylthiazol -2-yl)-2, 5-diphenyltetrazolium bromide [MTT]) assay, and absolute real-time-polymerase chain reaction (RT-PCR) were done to assess Bax and Bcl-2 genes expression, as molecular studies.
Results: MTT assay results revealed that the tilorone tissue culture IC
Conclusions: Based on these results, it appeared that this agent could be a good candidate for further evaluation as effective chemotherapy acting through the induction of apoptosis in hepatoma. The cell death caused through bacterial supernatant was rather necrosis than apoptosis.

Xie Q, Wang S, Zhao Y, et al.
MicroRNA-216a suppresses the proliferation and migration of human breast cancer cells via the Wnt/β-catenin signaling pathway.
Oncol Rep. 2019; 41(5):2647-2656 [PubMed] Free Access to Full Article Related Publications
The aim of the present study was to investigate the potential anticancer effects of microRNA-216a on the growth of human breast cancer and the possible underlying mechanisms. The results demonstrated that serum microRNA-216a was significantly decreased in patients with breast cancer compared with healthy controls. MicroRNA-216a overexpression led to a decrease in cell proliferation and migration, as well as increases in apoptosis, caspase-3/8 activities, Bax expression and p53 protein expression in MCF-7 cells. It was also revealed that microRNA-216a suppressed Wnt and β-catenin expression in MCF-7 cells. The anticancer effects of microRNA-216a were reversed by anti-microRNA-216a by promoting the Wnt/β-catenin signaling pathway. Inactivation of the Wnt pathway increased the anticancer effects of microRNA-216a in MCF-7 cells. Collectively, the results of the present study indicated that microRNA-216a suppressed the growth of human breast cancer cells by targeting the Wnt/β‑catenin signaling pathway.

Zhao X, Fan J, Wu P, et al.
Chronic chemotherapy with paclitaxel nanoparticles induced apoptosis in lung cancer in vitro and in vivo.
Int J Nanomedicine. 2019; 14:1299-1309 [PubMed] Free Access to Full Article Related Publications
Aim: Paclitaxel (PTX) is an effective antitumor drug. Previous research demonstrated that paclitaxel nanoparticles (PTX-NPs) exhibited the greatest antitumor effect at 15 hours after light onset (15 HALO), but the mechanism in chronic chemotherapy is still unknown. In our study, we investigated whether PTX-NPs regulated Period2 (Per2) during chronic chemotherapy to induce apoptosis in vivo and in vitro.
Methods: To improve the antitumor effect and reduce organ damage induced by PTX treatment, PTX-NPs were prepared using a film dispersion method. Then, A549 cells were treated with PTX-NPs at 0, 5, 10, 15, and 20 HALO. An annexin/PI V-FITC apoptosis kit was measured for apoptosis, and PI was analyzed for cell cycle. The relative mechanism was detected by RT-PCR and Western blotting. Tumor volume and weight were measured to evaluate the antitumor effect of the PTX-NPs, and H&E staining was performed to assess organ damage.
Results: Cell cycle analysis demonstrated that PTX-NPs blocked cell cycle in G2 phase and that the ratio of cell death was significantly increased in A549 cells, while the ratios of cells in G2 phase and of apoptotic cells were highest at 15 HALO. Evaluation of in vivo antitumor activity revealed that PTX-NPs inhibited tumor growth and decreased tumor weight at 15 HALO. RT-PCR and Western blotting demonstrated that PTX-NPs upregulated Per2 mRNA and protein expression, and the highest Per2 expression was observed at 15 HALO in vivo and in vitro. Meanwhile, Bax mRNA and protein expression was upregulated, while Bcl-2 mRNA and protein expression was downregulated after PTX-NPs treatment in vivo. Moreover, H&E staining revealed that PTX-NPs reduced liver damage at 15 HALO.
Conclusion: PTX-NPs exhibited the most effective antitumor activity and reduced liver damage at 15 HALO through upregulation of Per2 expression to induce apoptosis in vivo and in vitro.

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