BIRC3

Gene Summary

Gene:BIRC3; baculoviral IAP repeat containing 3
Aliases: AIP1, API2, MIHC, CIAP2, HAIP1, HIAP1, MALT2, RNF49, c-IAP2
Location:11q22
Summary:This gene encodes a member of the IAP family of proteins that inhibit apoptosis by binding to tumor necrosis factor receptor-associated factors TRAF1 and TRAF2, probably by interfering with activation of ICE-like proteases. The encoded protein inhibits apoptosis induced by serum deprivation but does not affect apoptosis resulting from exposure to menadione, a potent inducer of free radicals. It contains 3 baculovirus IAP repeats and a ring finger domain. Transcript variants encoding the same isoform have been identified. [provided by RefSeq, Aug 2011]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:baculoviral IAP repeat-containing protein 3
HPRD
Source:NCBIAccessed: 27 August, 2015

Ontology:

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 (1990-2015)
Graph generated 27 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.

Tag cloud generated 27 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (8)

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: BIRC3 (cancer-related)

Ishikawa H, Iwamuro M, Okada H, et al.
Recurrence after radiotherapy for gastric mucosa-associated lymphoid tissue (MALT) lymphoma with trisomy 18.
Intern Med. 2015; 54(8):911-6 [PubMed] Related Publications
A 36-year-old Japanese woman presented with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) in the stomach. The gastric lesions only partially improved after eradication therapy for Helicobacter pylori. A fluorescence in situ hybridization analysis revealed no fusion genes of API2-MALT1, although trisomy of chromosome 18 was identified. Radiation therapy was initiated to treat the gastric lymphoma lesions, resulting in complete remission. However, MALT lymphoma recurred in the stomach 16 months later. This case indicates that intensive follow-up is required for MALT lymphoma associated with chromosomal aberrations in order to detect early relapse.

Lechuga S, Baranwal S, Ivanov AI
Actin-interacting protein 1 controls assembly and permeability of intestinal epithelial apical junctions.
Am J Physiol Gastrointest Liver Physiol. 2015; 308(9):G745-56 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
Adherens junctions (AJs) and tight junctions (TJs) are crucial regulators of the integrity and restitution of the intestinal epithelial barrier. The structure and function of epithelial junctions depend on their association with the cortical actin cytoskeleton that, in polarized epithelial cells, is represented by a prominent perijunctional actomyosin belt. The assembly and stability of the perijunctional cytoskeleton is controlled by constant turnover (disassembly and reassembly) of actin filaments. Actin-interacting protein (Aip) 1 is an emerging regulator of the actin cytoskeleton, playing a critical role in filament disassembly. In this study, we examined the roles of Aip1 in regulating the structure and remodeling of AJs and TJs in human intestinal epithelium. Aip1 was enriched at apical junctions in polarized human intestinal epithelial cells and normal mouse colonic mucosa. Knockdown of Aip1 by RNA interference increased the paracellular permeability of epithelial cell monolayers, decreased recruitment of AJ/TJ proteins to steady-state intercellular contacts, and attenuated junctional reassembly in a calcium-switch model. The observed defects of AJ/TJ structure and functions were accompanied by abnormal organization and dynamics of the perijunctional F-actin cytoskeleton. Moreover, loss of Aip1 impaired the apico-basal polarity of intestinal epithelial cell monolayers and inhibited formation of polarized epithelial cysts in 3-D Matrigel. Our findings demonstrate a previously unanticipated role of Aip1 in regulating the structure and remodeling of intestinal epithelial junctions and early steps of epithelial morphogenesis.

Sutton LA, Rosenquist R
Clonal evolution in chronic lymphocytic leukemia: impact of subclonality on disease progression.
Expert Rev Hematol. 2015; 8(1):71-8 [PubMed] Related Publications
In recent years, next-generation sequencing has unraveled the molecular landscape in chronic lymphocytic leukemia with the discovery of a number of recurrently mutated genes. Mutations in several of these genes, such as NOTCH1, SF3B1 and BIRC3, are linked to a more aggressive disease with early disease progression, short time-to-first-treatment and even chemorefractoriness. Although in its infancy, we have also begun to understand the complex dynamics of subclonal diversity and its impact on disease outcome. From pioneering studies, we know that certain genetic events are found in the majority of chronic lymphocytic leukemia cells and are considered as 'clonal driver mutations' (e.g., +12, 13q-), whereas others, present only in a fraction of the tumor, are deemed to be 'subclonal driver mutations' for example, TP53 and SF3B1. Over the coming years, we need to gain a deeper insight into the dynamics of this subclonal architecture to understand how, at an individual level, chronic lymphocytic leukemia patients should be followed, which will be particularly relevant as novel targeted therapies begin to emerge.

Mi C, Shi H, Ma J, et al.
Celastrol induces the apoptosis of breast cancer cells and inhibits their invasion via downregulation of MMP-9.
Oncol Rep. 2014; 32(6):2527-32 [PubMed] Related Publications
Celastrol is a quinone methide triterpene derived from Tripterygium wilfordii Hook F., a plant used in traditional medicine. In the present study, we reported that celastrol potentiated tumor necrosis factor-α (TNF-α)-induced apoptosis, affected activation of caspase-8, caspase-3 and PARP cleavage, and inhibited the expression of anti-apoptotic proteins such as cellular inhibitor of apoptosis protein 1 and 2 (cIAP1 and cIAP2), cellular FLICE-inhibitory protein (FLIP), and B-cell lymphoma 2 (Bcl-2). In addition, celastrol significantly reduced the invasion of MDA-MB-231 human breast cancer cells after TNF-α stimulation. As matrix metalloproteinase-9 (MMP-9) plays a critical role in tumor metastasis, we analyzed its expression with celastrol treatment. Western blot analysis and real-time PCR showed that celastrol dose-dependently suppressed TNF-α-induced MMP-9 gene expression at both the mRNA and protein levels in MDA-MB-231 cells. Taken together, our findings indicate that celastrol may be a potential candidate for breast cancer chemotherapy.

Hu R, Li J, Liu Z, et al.
GDC-0152 induces apoptosis through down-regulation of IAPs in human leukemia cells and inhibition of PI3K/Akt signaling pathway.
Tumour Biol. 2015; 36(2):577-84 [PubMed] Related Publications
The inhibitor of apoptosis proteins (IAPs) is closely related to leukemia apoptosis. The present study was undertaken to determine the molecular mechanisms by which GDC-0152, an IAP inhibitor, induces apoptosis in human leukemia cells (K562 and HL60 cells). GDC-0152 inhibited the proliferation of K562 and HL60 cells in a dose- and time-dependent manner, which was largely attributed to intrinsic apoptosis. GDC-0152 down-regulated the IAPs including X-linked inhibitor of apoptosis protein (XIAP), cellular inhibitor of apoptosis protein-1 (cIAP1), and cellular inhibitor of apoptosis protein-2 (cIAP2) expression and induced the activation of caspase-9 and caspase-3. GDC-0152-induced cell proliferation inhibition in K562 cells was prevented by pan-caspase inhibitor. GDC-0152 also inhibited PI3K and Akt expression in K562 and HL60 cells. Taken together, these findings suggest that GDC-0152 results in human leukemia apoptosis through caspase-dependent mechanisms involving down-regulation of IAPs and inhibition of PI3K/Akt signaling.

Beaudin SG, Robilotto S, Welsh J
Comparative regulation of gene expression by 1,25-dihydroxyvitamin D3 in cells derived from normal mammary tissue and breast cancer.
J Steroid Biochem Mol Biol. 2015; 148:96-102 [PubMed] Related Publications
Previous genomic profiling of immortalized, non-tumorigenic human breast epithelial cells identified a set of 1,25-dihydroxyvitamin D3 (1,25D) regulated genes with potential relevance to breast cancer prevention. In this report, we characterized the effect of 1,25D on a subset of these genes in six cell lines derived from mammary tissue and breast cancers. Non-tumorigenic cell lines included hTERT-HME1, HME and MCF10A cells which are often used to model normal breast epithelial cells. Breast cancer cell lines included MCF7 cells (a model of early stage, estrogen-dependent disease), DCIS.com cells (a derivative of MCF10A cells that models in situ breast cancer) and Hs578T cells (a model of metastatic disease). All of these cell lines express the vitamin D receptor (VDR) and exhibit anti-cancer responses to 1,25D such as changes in proliferation, apoptosis, metabolism, or invasion. Our comparative data demonstrate highly variable responses to 1,25D (100nM, 24h) between the cell lines. In both hTERT-HME1 and HME cell lines, CYP24A1, SLC1A1 and ITGB3 were up-regulated whereas KDR, GLUL and BIRC3 were down-regulated in response to 1,25D. In contrast, no changes in SLC1A1, ITGB3 or GLUL expression were detected in 1,25D treated MCF10A cells although KDR and BIRC3 were down-regulated by 1,25D. The effects of 1,25D on these genes in the breast cancer cell lines were blunted, with the DCIS.com cells exhibiting the most similar responses to the immortalized hTERT-HME1 and HME cells. The differences in cellular responses were not due to general impairment in VDR function as robust CYP24A1 induction was observed in all cell lines. Thus, our data indicate that the genomic changes induced by 1,25D are highly cell-type specific even in model cell lines derived from the same tissue. The implication of these findings is that genomic responses to changes in vitamin D status in vivo are likely to be distinct from individual to individual, particularly in neoplastic tissue. This article is part of a Special Issue entitled '17th Vitamin D Workshop'.

Samuel T, Fadlalla K, Gales DN, et al.
Variable NF-κB pathway responses in colon cancer cells treated with chemotherapeutic drugs.
BMC Cancer. 2014; 14:599 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
BACKGROUND: The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway is activated in cells exposed to various stimuli, including those originating on the cell surface or in the nucleus. Activated NF-κB signaling is thought to enhance cell survival in response to these stimuli, which include chemotherapy and radiation. In the present effort, we determined which anticancer drugs preferentially activate NF-κB in colon cancer cells.
METHODS: NF-κB reporter cells were established and treated with 5-fluorouracil (5-FU, DNA/RNA damaging), oxaliplatin (DNA damaging), camptothecin (CTP, topoisomerase inhibitor), phleomycin (radiomimetic), or erlotinib (EGFR inhibitor). The activation of NF-κB was assessed by immunofluorescence for p65 translocation, luciferase assays, and downstream targets of NF-κB activation (cIAP2, and Bcl-XL) were evaluated by immunoblotting, by ELISA (CXCL8 and IL-6 in culture supernatants), or by gene expression analysis.
RESULTS: Colon cancer cells responded variably to different classes of therapeutic agents, and these agents initiated variable responses among different cell types. CPT activated NF-κB in SW480 colon cancer cells in a dose-dependent manner, but not in HCT116 cells that were either wild-type or deficient for p53. In SW480 colon cancer cells, NF-κB activation by CPT was accompanied by secretion of the cytokine CXCL8, but not by up-regulation of the anti-apoptotic genes, cIAP2 or Bcl-XL. On the contrary, treatment of HCT116 cells with CPT resulted in up-regulation of CXCR2, a receptor for CXCL8, without an increase in cytokine levels. In SW480 cells, NF-κB reporter activity, but not cytokine secretion, was inhibited by SM-7368, an NF-κB inhibitor.
CONCLUSION: The results show that, in response to cancer therapeutic agents, NF-κB activation varies with the cellular make up and that drug-induced NF-κB activation may be functionally uncoupled from anti-apoptotic outcomes found for other stimuli. Some cancer cells in a heterogeneous tumor tissue may, under therapeutic pressure, release soluble factors that have paracrine activity on neighboring cells that express the cognate receptors.

Beach JA, Nary LJ, Hovanessian R, Medh RD
Correlation of glucocorticoid-mediated E4BP4 upregulation with altered expression of pro- and anti-apoptotic genes in CEM human lymphoblastic leukemia cells.
Biochem Biophys Res Commun. 2014; 451(3):382-8 [PubMed] Article available free on PMC after 29/08/2015 Related Publications
In Caenorhabditiselegans, motorneuron apoptosis is regulated via a ces-2-ces-1-egl-1 pathway. We tested whether human CEM lymphoblastic leukemia cells undergo apoptosis via an analogous pathway. We have previously shown that E4BP4, a ces-2 ortholog, mediates glucocorticoid (GC)-dependent upregulation of BIM, an egl-1 ortholog, in GC-sensitive CEM C7-14 cells and in CEM C1-15mE#3 cells, which are sensitized to GCs by ectopic expression of E4BP4. In the present study, we demonstrate that the human ces-1 orthologs, SLUG and SNAIL, are not significantly repressed in correlation with E4BP4 expression. Expression of E4BP4 homologs, the PAR family genes, especially HLF, encoding a known anti-apoptotic factor, was inverse to that of E4BP4 and BIM. Expression of pro- and anti-apoptotic genes in CEM cells was analyzed via an apoptosis PCR Array. We identified BIRC3 and BIM as genes whose expression paralleled that of E4BP4, while FASLG, TRAF4, BCL2A1, BCL2L1, BCL2L2 and CD40LG as genes whose expression was opposite to that of E4BP4.

Luk SU, Xue H, Cheng H, et al.
The BIRC6 gene as a novel target for therapy of prostate cancer: dual targeting of inhibitors of apoptosis.
Oncotarget. 2014; 5(16):6896-908 [PubMed] Article available free on PMC after 29/08/2015 Related Publications
Treatment resistance, the major challenge in the management of advanced prostate cancer, is in part based on resistance to apoptosis. The Inhibitor of Apoptosis (IAP) family is thought to play key roles in survival and drug resistance of cancer via inhibition of apoptosis. Of the IAP family members, cIAP1, cIAP2, XIAP and survivin are known to be up-regulated in prostate cancer. BIRC6, a much less studied IAP member, was recently shown to be elevated in castration-resistant prostate cancer (CRPC). In the present study, we showed a correlation between elevated BIRC6 expression in clinical prostate cancer specimens and poor patient prognostic factors, as well as co-upregulation of certain IAP members. In view of this, we designed antisense oligonucleotides that simultaneously target BIRC6 and another co-upregulated IAP member (dASOs). Two dASOs, targeting BIRC6+cIAP1 and BIRC6+survivin, showed substantial inhibition of CRPC cells proliferation, exceeding that obtained with single BIRC6 targeting. The growth inhibition was associated with increased apoptosis, cell cycle arrest and suppression of NFkB activation. Moreover, treatment with both dASOs led to significantly lower viable tumor volume in vivo, without major host toxicity. This study shows that BIRC6-based dual IAP-targeting ASOs represent potential novel therapeutic agents against advanced prostate cancer.

Puiggros A, Blanco G, Espinet B
Genetic abnormalities in chronic lymphocytic leukemia: where we are and where we go.
Biomed Res Int. 2014; 2014:435983 [PubMed] Article available free on PMC after 29/08/2015 Related Publications
Chromosomal abnormalities in chronic lymphocytic leukemia (CLL) are detected in up to 80% of patients. Among them, deletions of 11q, 13q, 17p, and trisomy 12 have a known prognostic value and play an important role in CLL pathogenesis and evolution, determining patients outcome and therapeutic strategies. Standard methods used to identify these genomic aberrations include both conventional G-banding cytogenetics (CGC) and fluorescence in situ hybridization (FISH). Although FISH analyses have been implemented as the gold standard, CGC allows the identification of chromosomal translocations and complex karyotypes, the latest associated with poor outcome. Genomic arrays have a higher resolution that allows the detection of cryptic abnormalities, although these have not been fully implemented in routine laboratories. In the last years, next generation sequencing (NGS) methods have identified a wide range of gene mutations (e.g., TP53, NOTCH1, SF3B1, and BIRC3) which have improved our knowledge about CLL development, allowing us to refine both the prognostic subgroups and better therapeutic strategies. Clonal evolution has also recently arisen as a key point in CLL, integrating cytogenetic alterations and mutations in a dynamic model that improve our understanding about its clinical course and relapse.

Bour T, Yang X, Li W, et al.
Differential effects of antofine N-oxide on solid tumor and leukemia cells.
Anticancer Agents Med Chem. 2014; 14(10):1315-23 [PubMed] Related Publications
We have studied the anti-cancer activities of antofine N-oxide isolated and purified from the medicinal plant Cynanchum vincetoxicum. Antofine N-oxide displayed a strong inhibitory effect on several solid tumor cell lines (glioblastoma, breast carcinoma and lung carcinoma) and on a T-cell leukemia cell line. Remarkably, its cytotoxic effect was considerably weaker in non-cancer cells. Antofine N-oxide was found to inhibit proliferation of the solid tumor cells whereas it caused apoptotic cell death in the leukemia cells. A microarray analysis after a short treatment revealed that the number of differentially expressed genes was considerably higher in solid tumor than in leukemia cells. Up-regulated genes in the three solid tumor cell lines include genes related to TNFα signaling, of which TNFα was among the most significantly induced. A functional analysis revealed that TNFR1 signaling was most likely activated in the solid tumor cells. The increased mRNA levels of several genes of this pathway (namely TNFα, TNFAIP3 and BIRC3) were confirmed by real-time quantitative PCR after different treatment durations. Finally a slight inhibition of NFκB-mediated transcription was observed in the same cells. Together our results suggest that inhibition of cell proliferation in solid tumor cells essentially occurs through TNFα signaling whereas this pathway is not activated in leukemia cells. Apoptotic cell death in the latter is induced by a distinct yet unknown pathway.

Rizzo D, Chauzeix J, Trimoreau F, et al.
IgM peak independently predicts treatment-free survival in chronic lymphocytic leukemia and correlates with accumulation of adverse oncogenetic events.
Leukemia. 2015; 29(2):337-45 [PubMed] Related Publications
We examined the significance of IgM peaks in chronic lymphocytic leukemia (CLL), including its association with newly reported MYD88, BIRC3, NOTCH1 and SF3B1 mutations. A total of 27, 25, 41 and 57 patients with monoclonal IgM or IgG peaks (IgM and IgG groups), hypogammaglobulinemia (Hypo-γ group) and normal immunoglobulin serum levels (normal-γ group) were, respectively, included. IgM peaks were mainly associated with Binet stage C and the del(17p). Biased usage of IGHV3-48 was shared by both IgM and IgG groups. IGHV3-74 and IGHV4-39 gene rearrangements were specific for IgM and IgG peaks, respectively. SF3B1, NOTCH1, MYD88 and BIRC3 mutation frequencies were 12%, 4%, 2% and 2%, respectively, being over-represented in IgM, IgG and Hypo-γ groups for SF3B1, and being equal between normal-γ and IgM groups for MYD88. Overall, 76%, 87%, 49% and 42% of cases from IgM, IgG, Hypo-γ and normal-γ groups had at least one intermediate or poor prognosis genetic marker, respectively. By multivariate analysis, IgM peaks were associated with shorter treatment-free survival independently from any other univariate poor prognosis biological parameters, including IgG peaks, Hypo-γ, IGHV status, SF3B1 mutations, cytogenetics and lymphocytosis. Therefore, as with IgG peaks, IgM peaks aggravated the natural course of CLL, with increased accumulation of adverse genetic events.

Baliakas P, Hadzidimitriou A, Sutton LA, et al.
Recurrent mutations refine prognosis in chronic lymphocytic leukemia.
Leukemia. 2015; 29(2):329-36 [PubMed] Related Publications
Through the European Research Initiative on chronic lymphocytic leukemia (CLL) (ERIC), we screened 3490 patients with CLL for mutations within the NOTCH1 (n=3334), SF3B1 (n=2322), TP53 (n=2309), MYD88 (n=1080) and BIRC3 (n=919) genes, mainly at diagnosis (75%) and before treatment (>90%). BIRC3 mutations (2.5%) were associated with unmutated IGHV genes (U-CLL), del(11q) and trisomy 12, whereas MYD88 mutations (2.2%) were exclusively found among M-CLL. NOTCH1, SF3B1 and TP53 exhibited variable frequencies and were mostly enriched within clinically aggressive cases. Interestingly, as the timespan between diagnosis and mutational screening increased, so too did the incidence of SF3B1 mutations; no such increase was observed for NOTCH1 mutations. Regarding the clinical impact, NOTCH1 mutations, SF3B1 mutations and TP53 aberrations (deletion/mutation, TP53ab) correlated with shorter time-to-first-treatment (P<0.0001) in 889 treatment-naive Binet stage A cases. In multivariate analysis (n=774), SF3B1 mutations and TP53ab along with del(11q) and U-CLL, but not NOTCH1 mutations, retained independent significance. Importantly, TP53ab and SF3B1 mutations had an adverse impact even in U-CLL. In conclusion, we support the clinical relevance of novel recurrent mutations in CLL, highlighting the adverse impact of SF3B1 and TP53 mutations, even independent of IGHV mutational status, thus underscoring the need for urgent standardization/harmonization of the detection methods.

Chen L, Zhang X, Chen J, et al.
NF-κB plays a key role in microcystin-RR-induced HeLa cell proliferation and apoptosis.
Toxicon. 2014; 87:120-30 [PubMed] Related Publications
Microcystins (MCs) are well-known cyanobacterial toxins produced in eutrophic waters and can act as potential carcinogens and have caused serious risk to human health. However, pleiotropic even paradoxical actions of cells exposure to MCs have been reported, and the mechanisms of MC-induced tumorigenesis and apoptosis are still unknown. In this study, we performed the first comprehensive in vitro investigation on carcinogenesis associated with nuclear factor kappa B (NF-κB) and its downstream genes in HeLa cells (Human cervix adenocarcinoma cell line from epithelial cells) exposure to MC-RR. HeLa cells were treated with 0, 20, 40, 60, and 80 µg/mL MC-RR for 4, 8, 12, and 24 h. HeLa cells presented dualistic responses to different doses of MCs. CCK8 assay showed that MC-RR exposure evidently enhanced cell viability of HeLa cells at lower MCs doses. Cell cycle and apoptosis analysis revealed that lower MCs doses promoted G1/S transition and cell proliferation while higher doses of MCs induced apoptosis, with a dose-dependent manner. Electrophoretic mobility shift assay (EMSA) revealed that MC-RR could increase/decrease NF-κB activity at lower/higher MC-RR doses, respectively. Furthermore, the expression of NF-κB downstream target genes including c-FLIP, cyclinD1, c-myc, and c-IAP2 showed the same variation trend as NF-κB activity both at mRNA and protein levels, which were induced by lower doses of MC-RR and suppressed by higher doses. Our data verified for the first time that NF-κB pathway may mediate MC-induced cell proliferation and apoptosis and provided a better understanding of the molecular mechanism for potential carcinogenicity of MC-RR.

Saba N, Wiestner A
Do mantle cell lymphomas have an 'Achilles heel'?
Curr Opin Hematol. 2014; 21(4):350-7 [PubMed] Article available free on PMC after 29/08/2015 Related Publications
PURPOSE OF REVIEW: Mantle cell lymphoma (MCL) is a mature B-cell malignancy that continues to have a high mortality rate. In this article, we discuss key pathogenic pathways in MCL biology and their possible therapeutic targeting.
RECENT FINDINGS: In addition to cyclin-D1, the transcription factor SOX-11 emerged as a common characteristic of MCL. Genomic studies have identified a number of recurrently mutated genes; in order of descending frequency these include ATM, CCND1, UBR5, TP53, BIRC3, NOTCH1/2 and TRAF2. However, no clear oncogenic driver has been identified. In contrast, several observations indicate that MCL cells are antigen-experienced cells and that the tumor microenvironment and B-cell receptor engagement are important. This is underscored by the impressive clinical responses achieved with the Bruton's tyrosine kinase inhibitor ibrutinib. Recently identified activating mutations in the noncanonical nuclear factor-kappa B pathway could give rise to ibrutinib resistance. Poly-ADP ribose polymerase and aurora kinase inhibitors may be synthetic lethal with the common aberrations in DNA damage pathways found in MCL. Also, ABT-199, a potent and selective inhibitor of B-cell lymphoma 2, has promising activity in early studies.
SUMMARY: MCL is a heterogeneous disease, and no single Achilles heel has been identified. Nevertheless, genomic, molecular and clinical studies have revealed vulnerabilities that can be exploited for effective therapy.

Jönsson JM, Bartuma K, Dominguez-Valentin M, et al.
Distinct gene expression profiles in ovarian cancer linked to Lynch syndrome.
Fam Cancer. 2014; 13(4):537-45 [PubMed] Article available free on PMC after 29/08/2015 Related Publications
Ovarian cancer linked to Lynch syndrome represents a rare subset that typically presents at young age as early-stage tumors with an overrepresentation of endometrioid and clear cell histologies. We investigated the molecular profiles of Lynch syndrome-associated and sporadic ovarian cancer with the aim to identify key discriminators and central tumorigenic mechanisms in hereditary ovarian cancer. Global gene expression profiling using whole-genome c-DNA-mediated Annealing, Selection, extension, and Ligation was applied to 48 histopathologically matched Lynch syndrome-associated and sporadic ovarian cancers. Lynch syndrome-associated and sporadic ovarian cancers differed by 349 significantly deregulated genes, including PTPRH, BIRC3, SHH and TNFRSF6B. The genes involved were predominantly linked to cell growth, proliferation, and cell-to-cell signaling and interaction. When stratified for histologic subtype, hierarchical clustering confirmed distinct differences related to heredity in the endometrioid and serous subtypes. Furthermore, separate clustering was achieved in an independent, publically available data set. The distinct genetic signatures in Lynch syndrome-associated and sporadic ovarian cancers point to alternative preferred tumorigenic routes and suggest that genetic discriminators may be relevant for molecular diagnostics and targeted therapeutics.

Kim EO, Kwon TK, Choi SW
Diferuloylputrescine, a predominant phenolic amide in corn bran, potently induces apoptosis in human leukemia U937 cells.
J Med Food. 2014; 17(5):519-26 [PubMed] Related Publications
The purpose of this study was to investigate how proliferation and apoptosis in human leukemia U937 cells are affected by four hydroxycinnamic acid derivatives (HCADs) in corn (Zea mays L.) bran: p-coumaric (CA), ferulic acids (FA), dicoumaroylputrescine (DCP), and diferuloylputrescine (DFP). Of the four HCADs, DFP dose dependently exerted the strongest cytotoxic effect and induction of apoptosis in the U937 cells. In addition, DFP induced distinct morphological changes characteristic of cellular apoptosis, such as chromatin condensation, apoptotic bodies, and DNA fragmentations. The DFP-induced apoptosis was also associated with released cytochrome c in the cytosol with activation of caspase 3, together with the downregulation of anti-apoptotic proteins, including XIAP and cIAP2, Bcl-2, and Mcl-1. Finally, the DFP-induced apoptosis was a cell-specific response in leukemia cells, as compared with those of other cancer cells, such as Caki, HT29, SK-Hep1, and MDA-MB231. Thus, these results suggest that DFP may be useful as a potential source of natural antileukemic agents.

Zhang JS, Herreros-Villanueva M, Herreros-Vilanueva M, et al.
Differential activity of GSK-3 isoforms regulates NF-κB and TRAIL- or TNFα induced apoptosis in pancreatic cancer cells.
Cell Death Dis. 2014; 5:e1142 [PubMed] Article available free on PMC after 29/08/2015 Related Publications
While TRAIL is a promising anticancer agent due to its ability to selectively induce apoptosis in neoplastic cells, many tumors, including pancreatic ductal adenocarcinoma (PDA), display intrinsic resistance, highlighting the need for TRAIL-sensitizing agents. Here we report that TRAIL-induced apoptosis in PDA cell lines is enhanced by pharmacological inhibition of glycogen synthase kinase-3 (GSK-3) or by shRNA-mediated depletion of either GSK-3α or GSK-3β. In contrast, depletion of GSK-3β, but not GSK-3α, sensitized PDA cell lines to TNFα-induced cell death. Further experiments demonstrated that TNFα-stimulated IκBα phosphorylation and degradation as well as p65 nuclear translocation were normal in GSK-3β-deficient MEFs. Nonetheless, inhibition of GSK-3β function in MEFs or PDA cell lines impaired the expression of the NF-κB target genes Bcl-xL and cIAP2, but not IκBα. Significantly, the expression of Bcl-xL and cIAP2 could be reestablished by expression of GSK-3β targeted to the nucleus but not GSK-3β targeted to the cytoplasm, suggesting that GSK-3β regulates NF-κB function within the nucleus. Consistent with this notion, chromatin immunoprecipitation demonstrated that GSK-3 inhibition resulted in either decreased p65 binding to the promoter of BIR3, which encodes cIAP2, or increased p50 binding as well as recruitment of SIRT1 and HDAC3 to the promoter of BCL2L1, which encodes Bcl-xL. Importantly, depletion of Bcl-xL but not cIAP2, mimicked the sensitizing effect of GSK-3 inhibition on TRAIL-induced apoptosis, whereas Bcl-xL overexpression ameliorated the sensitization by GSK-3 inhibition. These results not only suggest that GSK-3β overexpression and nuclear localization contribute to TNFα and TRAIL resistance via anti-apoptotic NF-κB genes such as Bcl-xL, but also provide a rationale for further exploration of GSK-3 inhibitors combined with TRAIL for the treatment of PDA.

Chiaretti S, Marinelli M, Del Giudice I, et al.
NOTCH1, SF3B1, BIRC3 and TP53 mutations in patients with chronic lymphocytic leukemia undergoing first-line treatment: correlation with biological parameters and response to treatment.
Leuk Lymphoma. 2014; 55(12):2785-92 [PubMed] Related Publications
In chronic lymphocytic leukemia, NOTCH1, SF3B1, BIRC3 and TP53 disruptions are recurrent and affect survival. To define their incidence and clinical impact in patients undergoing first-line treatment, we evaluated 163 cases enrolled in the GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) LLC0405 protocol (fludarabine plus alemtuzumab or fludarabine plus cyclophosphamide), for young patients, or in the ML21445 protocol (chlorambucil plus rituximab), for elderly patients. NOTCH1, SF3B1, BIRC3 and TP53 disruptions were detected in 15.9%, 12.2%, 8.6% and 10.4% of cases. NOTCH1 mutations correlated with a shorter treatment-free interval (p = 0.058), an unmutated immunoglobulin heavy variable gene (IGHV) status (p < 0.0001), CD38 and ZAP-70 expression (p = 0.0025 and 0.026, respectively) and trisomy 12 (p = 0.0028), SF3B1 mutations with an unmutated IGHV status (p = 0.02), and BIRC3 disruptions with an unmutated IGHV configuration (p = 0.01) and 11q deletion (p < 0.0001). NOTCH1 and SF3B1 did not appear to impact on overall response, while an inferior response was observed for BIRC3- and TP53-disrupted cases in the LLC0405 and ML21445 protocols, respectively. Progression-free survival, evaluable in the LLC0405 protocol - not affected by NOTCH1, SF3B1 and TP53 - appeared inferior for BIRC3 disruption. NOTCH1 and SF3B1 mutations may be overcome by aggressive regimens, while BIRC3 might impact on outcome also in intensive regimens.

Rose-Zerilli MJ, Forster J, Parker H, et al.
ATM mutation rather than BIRC3 deletion and/or mutation predicts reduced survival in 11q-deleted chronic lymphocytic leukemia: data from the UK LRF CLL4 trial.
Haematologica. 2014; 99(4):736-42 [PubMed] Article available free on PMC after 29/08/2015 Related Publications
ATM mutation and BIRC3 deletion and/or mutation have independently been shown to have prognostic significance in chronic lymphocytic leukemia. However, the relative clinical importance of these abnormalities in patients with a deletion of 11q encompassing the ATM gene has not been established. We screened a cohort of 166 patients enriched for 11q-deletions for ATM mutations and BIRC3 deletion and mutation and determined the overall and progression-free survival among the 133 of these cases treated within the UK LRF CLL4 trial. SNP6.0 profiling demonstrated that BIRC3 deletion occurred in 83% of 11q-deleted cases and always co-existed with ATM deletion. For the first time we have demonstrated that 40% of BIRC3-deleted cases have concomitant deletion and mutation of ATM. While BIRC3 mutations were rare, they exclusively occurred with BIRC3 deletion and a wild-type residual ATM allele. In 11q-deleted cases, we confirmed that ATM mutation was associated with a reduced overall and progression-free survival comparable to that seen with TP53 abnormalities, whereas BIRC3 deletion and/or mutation had no impact on overall and progression-free survival. In conclusion, in 11q-deleted patients treated with first-line chemotherapy, ATM mutation rather than BIRC3 deletion and/or mutation identifies a subgroup with a poorer outcome.

Wu P, Shi KJ, An JJ, et al.
The LEF1/CYLD axis and cIAPs regulate RIP1 deubiquitination and trigger apoptosis in selenite-treated colorectal cancer cells.
Cell Death Dis. 2014; 5:e1085 [PubMed] Article available free on PMC after 29/08/2015 Related Publications
Inhibitor-of-apoptosis protein (IAP) inhibitors have been reported to synergistically reduce cell viability in combination with a variety of chemotherapeutic drugs via targeted cellular IAP (cIAP) depletion. Here, we found that cIAP silencing sensitised colorectal cancer (CRC) cells to selenite-induced apoptosis. Upon selenite treatment, the K63-linked ubiquitin chains on receptor-interacting protein 1 (RIP1) were removed, leading to the formation of the death-inducing complex and subsequent caspase-8 activation. Although the ubiquitinases cIAP1 and cIAP2 were significantly downregulated after a 24-h selenite treatment, cylindromatosis (CYLD) deubiquitinase protein levels were marginally upregulated. Chromatin immunoprecipitation assays revealed that lymphoid enhancer factor-1 (LEF1) dissociated from the CYLD promoter upon selenite treatment, thus abolishing suppression of CYLD gene expression. We corroborated these findings in a CRC xenograft animal model using immunohistochemistry. Collectively, our findings demonstrate that selenite caused CYLD upregulation via LEF1 and cIAP downregulation, both of which contribute to the degradation of ubiquitin chains on RIP1 and subsequent caspase-8 activation and apoptosis. Importantly, our results identify a LEF1-binding site in the CYLD promoter as a potential target for combinational therapy as an alternative to cIAPs.

Paul P, Rajendran SK, Peuhu E, et al.
Novel action modality of the diterpenoid anisomelic acid causes depletion of E6 and E7 viral oncoproteins in HPV-transformed cervical carcinoma cells.
Biochem Pharmacol. 2014; 89(2):171-84 [PubMed] Related Publications
Cervical cancer, the second most common malignancy among women, is mainly caused by human papilloma virus (HPV) infection. In HPV-positive cervical cancer cells, the activity of p53 and the induction of p21 are inhibited by the HPV oncoproteins E6 and E7. Therefore, blocking the activity of E6 and E7 would serve as an important therapeutic target in these cancer cells. In this study, anisomelic acid (AA), a natural compound belonging to the same diterpenoid family of bioactive compounds as taxol, was found to deplete the E6 and E7 proteins in HPV-positive cervical cancer cells. Consequently, p53 and the p53-responsive gene, p21, were dramatically induced, leading to G2/M-phase cell cycle arrest. AA-mediated cell cycle arrest and p21 expression were canceled when p53 was down-regulated by p53-shRNA. AA also induced p53-independent intrinsic apoptosis by depletion of the cellular inhibitor of apoptosis protein 2 (cIAP2) whose proteosomal degradation is inhibited by E6. The in ovo chick embryo chorioallantoic membrane (CAM) assay showed that anisomelic acid inhibited the tumor growth of the cervical cancer SiHa cells. AA is revealed to hold a novel action modality based on specific targeting of the HPV oncoproteins, which restores p53-mediated growth arrest and induces apoptosis by terminating E6-mediated cIAP2 stabilization.

Benetatos CA, Mitsuuchi Y, Burns JM, et al.
Birinapant (TL32711), a bivalent SMAC mimetic, targets TRAF2-associated cIAPs, abrogates TNF-induced NF-κB activation, and is active in patient-derived xenograft models.
Mol Cancer Ther. 2014; 13(4):867-79 [PubMed] Related Publications
The acquisition of apoptosis resistance is a fundamental event in cancer development. Among the mechanisms used by cancer cells to evade apoptosis is the dysregulation of inhibitor of apoptosis (IAP) proteins. The activity of the IAPs is regulated by endogenous IAP antagonists such as SMAC (also termed DIABLO). Antagonism of IAP proteins by SMAC occurs via binding of the N-terminal tetrapeptide (AVPI) of SMAC to selected BIR domains of the IAPs. Small molecule compounds that mimic the AVPI motif of SMAC have been designed to overcome IAP-mediated apoptosis resistance of cancer cells. Here, we report the preclinical characterization of birinapant (TL32711), a bivalent SMAC-mimetic compound currently in clinical trials for the treatment of cancer. Birinapant bound to the BIR3 domains of cIAP1, cIAP2, XIAP, and the BIR domain of ML-IAP in vitro and induced the autoubiquitylation and proteasomal degradation of cIAP1 and cIAP2 in intact cells, which resulted in formation of a RIPK1:caspase-8 complex, caspase-8 activation, and induction of tumor cell death. Birinapant preferentially targeted the TRAF2-associated cIAP1 and cIAP2 with subsequent inhibition of TNF-induced NF-κB activation. The activity of a variety of chemotherapeutic cancer drugs was potentiated by birinapant both in a TNF-dependent or TNF-independent manner. Tumor growth in multiple primary patient-derived xenotransplant models was inhibited by birinapant at well-tolerated doses. These results support the therapeutic combination of birinapant with multiple chemotherapies, in particular, those therapies that can induce TNF secretion.

Messina M, Del Giudice I, Khiabanian H, et al.
Genetic lesions associated with chronic lymphocytic leukemia chemo-refractoriness.
Blood. 2014; 123(15):2378-88 [PubMed] Article available free on PMC after 29/08/2015 Related Publications
Fludarabine refractoriness (FR) represents an unsolved clinical problem of chronic lymphocytic leukemia (CLL) management. Although next-generation sequencing studies have led to the identification of a number of genes frequently mutated in FR-CLL, a comprehensive evaluation of the FR-CLL genome has not been reported. Toward this end, we studied 10 FR-CLLs by combining whole-exome sequencing and copy number aberration (CNA) analysis, which showed an average of 16.3 somatic mutations and 4 CNAs per sample. Screening of recurrently mutated genes in 48 additional FR-CLLs revealed that ~70% of FR-CLLs carry ≥1 mutation in genes previously associated with CLL clinical course, including TP53 (27.5%), NOTCH1 (24.1%), SF3B1 (18.9%), and BIRC3 (15.5%). In addition, this analysis showed that 10.3% of FR-CLL cases display mutations of the FAT1 gene, which encodes for a cadherin-like protein that negatively regulates Wnt signaling, consistent with a tumor suppressor role. The frequency of FAT1-mutated cases was significantly higher in FR-CLL than in unselected CLLs at diagnosis (10.3% vs 1.1%, P = .004), suggesting a role in the development of a high-risk phenotype. These findings have general implications for the mechanisms leading to FR and point to Wnt signaling as a potential therapeutic target in FR-CLL.

Campregher PV, Hamerschlak N
Novel prognostic gene mutations identified in chronic lymphocytic leukemia and their impact on clinical practice.
Clin Lymphoma Myeloma Leuk. 2014; 14(4):271-6 [PubMed] Related Publications
Chronic lymphocytic leukemia (CLL) is a lymphoid malignancy characterized by progressive accumulation of mature lymphocytes in the peripheral blood, bone marrow, liver, and lymphoid organs. Although most patients with CLL have an insidious clinical course, a subset of cases present with fast evolution and chemotherapy resistance, leading to high morbidity and mortality. Few clinically validated prognostic markers, such as TP53, are available for use in clinical practice to guide treatment decisions. Recently, several novel prognostically relevant molecular markers have been identified in CLL. We conducted a narrative literature review of the latest findings to evaluate the potential inclusion of these markers in the management of CLL cases.

Chan JK, Blansit K, Kiet T, et al.
The inhibition of miR-21 promotes apoptosis and chemosensitivity in ovarian cancer.
Gynecol Oncol. 2014; 132(3):739-44 [PubMed] Related Publications
BACKGROUND: MicroRNAs have been implicated in tumorigenesis, drug resistance, and prognosis in cancer. We investigated the role of microRNA-21 (miR-21) in regulating ovarian cancer drug resistance.
METHODS: We used parental and cisplatin resistant ovarian cell lines to demonstrate the role of miR-21 in drug resistance and investigated the gene targets of miR-21. Fresh tumor specimens were used to validate our in vitro findings.
RESULTS: Cisplatin resistant ovarian cells were four-fold more resistant compared to the parental cell line. MiR-21 was overexpressed in the resistant cell line on microRNA microarray, which was subsequently validated with qRT-PCR. Using anti-microRNA inhibitors, we demonstrated that miR-21 attenuation reversed the drug resistant phenotype in both the resistant and parental cell lines. The inhibition of miR-21 induced apoptosis based on annexin V-FITC immunostaining. Using Western blot analysis, miR-21 knockdown enhanced the expression of tumor suppressor PDCD4, and attenuated apoptosis inhibitor c-IAP2. Using 101 specimens from advanced ovarian cancer patients enrolled in The Cancer Genome Atlas, we found that women with tumors that overexpressed miR-21 were associated with a shorter progression-free survival.
CONCLUSION: Our data suggest that miR-21 regulates drug resistance via apoptosis and cellular survival pathways. Targeting miR-21 may have clinical utility in the treatment of resistant ovarian cancer.

Wang Q, Chen W, Bai L, et al.
Receptor-interacting protein 1 increases chemoresistance by maintaining inhibitor of apoptosis protein levels and reducing reactive oxygen species through a microRNA-146a-mediated catalase pathway.
J Biol Chem. 2014; 289(9):5654-63 [PubMed] Article available free on PMC after 29/08/2015 Related Publications
Although receptor-interacting protein 1 (RIP1) is well known as a key mediator in cell survival and death signaling, whether RIP1 directly contributes to chemotherapy response in cancer has not been determined. In this report, we found that, in human lung cancer cells, knockdown of RIP1 substantially increased cytotoxicity induced by the frontline anticancer therapeutic drug cisplatin, which has been associated with robust cellular reactive oxygen species (ROS) accumulation and enhanced apoptosis. Scavenging ROS dramatically protected RIP1 knockdown cells against cisplatin-induced cytotoxicity. Furthermore, we found that, in RIP1 knockdown cells, the expression of the hydrogen peroxide-reducing enzyme catalase was dramatically reduced, which was associated with increased miR-146a expression. Inhibition of microRNA-146a restored catalase expression, suppressed ROS induction, and protected against cytotoxicity in cisplatin-treated RIP1 knockdown cells, suggesting that RIP1 maintains catalase expression to restrain ROS levels in therapy response in cancer cells. Additionally, cisplatin significantly triggered the proteasomal degradation of cellular inhibitor of apoptosis protein 1 and 2 (c-IAP1 and c-IAP2), and X-linked inhibitor of apoptosis (XIAP) in a ROS-dependent manner, and in RIP1 knockdown cells, ectopic expression of c-IAP2 attenuated cisplatin-induced cytotoxicity. Thus, our results establish a chemoresistant role for RIP1 that maintains inhibitor of apoptosis protein (IAP) expression by release of microRNA-146a-mediated catalase suppression, where intervention within this pathway may be exploited for chemosensitization.

Foà R, Del Giudice I, Cuneo A, et al.
Chlorambucil plus rituximab with or without maintenance rituximab as first-line treatment for elderly chronic lymphocytic leukemia patients.
Am J Hematol. 2014; 89(5):480-6 [PubMed] Related Publications
In a phase II trial, we evaluated chlorambucil and rituximab (CLB-R) as first-line induction treatment with or without R as maintenance for elderly chronic lymphocytic leukemia (CLL) patients. Treatment consisted of eight 28-day cycles of CLB (8 mg/m(2) /day, days 1-7) and R (day 1 of cycle 3, 375 mg/m(2) ; cycles 4-8, 500 mg/m(2) ). Responders were randomized to 12 8-week doses of R (375 mg/m(2) ) or observation. As per intention-to-treat analysis, 82.4% (95% CI, 74.25-90.46%) of 85 patients achieved an overall response (OR), 16.5% a complete response (CR), 2.4% a CR with incomplete bone marrow recovery. The OR was similar across Binet stages (A 86.4%, B 81.6%, and C 78.6%) and age categories (60-64 years, 92.3%; 65-69, 85.2%; 70-74, 75.0%; ≥75, 81.0%). CLB-R was well tolerated. After a median follow-up of 34.2 months, the median progression-free survival (PFS) was 34.7 months (95% CI, 33.1-39.5). TP53 abnormalities, complex karyotype, and low CD20 gene expression predicted lack of response; SF3B1 mutation and BIRC3 disruption low CR rates. IGHV mutations significantly predicted PFS. R maintenance tended towards a better PFS than observation and was safe and most beneficial for patients in partial response and for unmutated IGHV cases. CLB-R represents a promising option for elderly CLL patients.

Omar HA, Arafa el-SA, Maghrabi IA, Weng JR
Sensitization of hepatocellular carcinoma cells to Apo2L/TRAIL by a novel Akt/NF-κB signalling inhibitor.
Basic Clin Pharmacol Toxicol. 2014; 114(6):464-71 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) cells are intrinsically resistant to tumour necrosis factor-related apoptosis ligand (Apo2L/TRAIL), in part, due to the compensatory activation of nuclear factor-kappaB (NF-κB). To broaden the clinical utilization of Apo2L/TRAIL in HCC, OSU-A9, a potent indole-3-carbinol-derived Akt/NF-κB signalling inhibitor was used to overcome the intrinsic resistance. The antitumour effects of OSU-A9, Apo2L/TRAIL and the therapeutic combination were assessed by MTT assay, caspase activation and PARP cleavage, and the synergistic interactions were determined by Calcusyn analysis. NF-κB reporter gene and RT-PCR were tested for the activation of NF-κB and the expression of death receptors (DR)4 and 5. OSU-A9 could sensitize HCC cells to Apo2L/TRAIL with high potency through down-regulation of Akt/NF-κB signalling. OSU-A9 dose-dependently reduced Akt phosphorylation and the expression and nuclear localization of RelA/p65, accompanied by parallel decreases in the expression of NF-κB target products, including Bcl-xL, Mcl-1, cIAP1, cIAP2 and survivin. Moreover, OSU-A9 increased DR5 expression through a reactive oxygen species (ROS)-dependent mechanism. Concertedly, these mechanisms underlie the synergistic interaction between OSU-A9 and Apo2L/TRAIL in mediating apoptotic death in HCC cells. The ability of OSU-A9 to accentuate Apo2L/TRAIL-induced apoptosis by inactivating Akt/NF-κB signalling might foster a promising therapeutic strategy for HCC.

Wu P, Cheng YW, Wang JY, et al.
Inhibition of MEK sensitizes gastric cancer cells to TRAIL-induced apoptosis.
Neoplasma. 2014; 61(2):136-43 [PubMed] Related Publications
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which has long been believed to be highly selective in inducing apoptosis in cancer cells, has turned out to be a molecule that induces a far more diverse range of effects. The aim of this study was to investigate whether or not ERK1/2 pathway is involved in antitumor effects of TRAIL on gastric cancer cells. In addition to activate the extrinsic and intrinsic apoptotic pathway, TRAIL also triggered the activation of ERK1/2. Inhibition of ERK1/2 signaling by MEK inhibitor U0126 promoted cell death via increased activation of caspases, drop in mitochondrial membrane potential and downregulation of XIAP, cIAP2 and Mcl-1. These results indicate that TRAIL-induced rapid activation of ERK1/2 may be a survival mechanism to struggle against TRAIL assault at the early stage, and inhibition of ERK1/2 signaling can sensitize gastric cancer cells to TRAIL-induced apoptosis.

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