MCL1

Gene Summary

Gene:MCL1; myeloid cell leukemia 1
Aliases: TM, EAT, MCL1L, MCL1S, Mcl-1, BCL2L3, MCL1-ES, bcl2-L-3, mcl1/EAT
Location:1q21
Summary:This gene encodes an anti-apoptotic protein, which is a member of the Bcl-2 family. Alternative splicing results in multiple transcript variants. The longest gene product (isoform 1) enhances cell survival by inhibiting apoptosis while the alternatively spliced shorter gene products (isoform 2 and isoform 3) promote apoptosis and are death-inducing. [provided by RefSeq, Oct 2010]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:induced myeloid leukemia cell differentiation protein Mcl-1
HPRD
Source:NCBIAccessed: 17 August, 2015

Ontology:

What does this gene/protein do?
Show (20)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 17 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.

  • MCL1
  • Neoplasm Proteins
  • Membrane Proteins
  • Chromosome 1
  • BCL2 protein
  • Validation Studies as Topic
  • Down-Regulation
  • Tumor Microenvironment
  • Nitrophenols
  • Acute Lymphocytic Leukaemia
  • Drug Synergism
  • Lung Cancer
  • Messenger RNA
  • Gene Expression Profiling
  • Piperazines
  • Antineoplastic Agents
  • Cell Proliferation
  • RT-PCR
  • Translocation
  • Proto-Oncogene Proteins
  • Chronic Lymphocytic Leukemia
  • Phosphorylation
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Apoptosis Regulatory Proteins
  • Paclitaxel
  • Western Blotting
  • Protein Kinase Inhibitors
  • Young Adult
  • Drug Resistance
  • Apoptosis
  • Dose-Response Relationship, Drug
  • MicroRNAs
  • Biphenyl Compounds
  • RNA Interference
  • Transcriptional Activation
  • Mutation
  • Retinoic Acid
  • Cancer Gene Expression Regulation
  • Tumor Suppressor Proteins
  • Cell Survival
  • siRNA
Tag cloud generated 17 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

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: MCL1 (cancer-related)

Grzegorek I, Zuba-Surma E, Chabowski M, et al.
Characterization of cells cultured from chylous effusion from a patient with sporadic lymphangioleiomyomatosis.
Anticancer Res. 2015; 35(6):3341-51 [PubMed] Related Publications
BACKGROUND: Lymphangioleiomyomatosis (LAM) is a progressive, rare interstitial lung disease that almost exclusively affects women. It is caused by a mutation in one of the tuberous sclerosis genes, TSC1 or TSC2, and constitutive activation of the mammalian target of rapamycin (mTOR) pathway in smooth muscle-like cells (LAM cells). The heightened proliferation and accumulation of LAM cells leads to the destruction of lung tissue.
MATERIALS AND METHODS: In the present study, we developed a cell line (S-LAM1) derived from a chylous effusion obtained from a patient with sporadic, pulmonary LAM and evaluated its phenotype using immunofluorescence, flow cytometry, and an image stream system. Ultrastructure was assessed using a transmission electron microscope. To assess the ability of LAM cells to move and migrate (which is strictly associated with the ability to metastasize), we carried-out a real-time polymerase chain reaction (PCR) array analysis of 84 genes involved in cell motility. In order to evaluate the effect of rapamycin, a natural inhibitor of mTOR kinase, on S-LAM1 cells, a sulforhodamine B cell viability assay was performed with different concentrations of rapamycin.
RESULTS AND CONCLUSION: The phenotype of these cells is consistent with the biology of LAM cells. S-LAM1 cells present combined smooth muscle, melanocytic, and lymphatic endothelium lineage, as well as the presence of mesenchymal differentiation markers. A particular pattern of gene expression, including high expression of ezrin (EZR), myosin heavy chain 10, non-muscle (MYH10), and myosin light chain kinase (MYLK) and a greatly decreased expression of supervillin (SVIL), when compared to controls, indicates a high potential motility activity, especially of cell spreading. Rapamycin significantly, although only partially, inhibited S-LAM1 cell proliferation in vitro, and should, perhaps, be considered in the future in combination with other agents.

Haug BH, Hald ØH, Utnes P, et al.
Exosome-like Extracellular Vesicles from MYCN-amplified Neuroblastoma Cells Contain Oncogenic miRNAs.
Anticancer Res. 2015; 35(5):2521-30 [PubMed] Related Publications
BACKGROUND: In recent years, evidence has accumulated indicating that both normal and cancer cells communicate via the release and delivery of macromolecules packed into extracellular membrane vesicles.
MATERIALS AND METHODS: We isolated nano-sized extracellular vesicles from MYCN-amplified neuroblastoma cell lines using ultracentrifugation and exosome precipitation (Exoquick) protocols. These vesicles were characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis and western blotting. Exosomal miRNA profiles were obtained using a reverse transcription-polymerase chain reaction (RT-PCR) ready-to-use panel measuring a total of 742 miRNAs.
RESULTS: In this study, we showed that MYCN-amplified neuroblastoma cell lines secrete populations of miRNAs inside small exosome-like vesicular particles. These particles were shown to be taken-up by recipient cells. By profiling the miRNA content, we demonstrated high expression of a group of established oncomirs in exosomes from two MYCN-amplified neuroblastoma cell lines. Despite the fact that other studies have demonstrated the ability of exosomal miRNAs both to repress mRNA targets and to stimulate Toll-like receptor-8 (TLR8) signaling in recipient cells, we did not observe these effects with exosomes from MYCN-amplified neuroblastoma cells. However, functional enrichment analysis reveals that mRNA targets of highly expressed exosomal miRNAs are associated with a range of cellular and molecular functions related to cell growth and cell death.
CONCLUSION: MYCN-amplified neuroblastoma cell lines secrete exosome-like particles containing oncogenic miRNAs. This work showed for the first time that neuroblastoma cells secrete exosome-like particles containing miRNAs with potential roles in cancer progression. These findings indicate a new way for MYCN-amplified neuroblastoma cells to interact with the tumor environment.

Yuan Y, Zhang X, Zeng X, et al.
Glutathione-mediated release of functional miR-122 from gold nanoparticles for targeted induction of apoptosis in cancer treatment.
J Nanosci Nanotechnol. 2014; 14(8):5620-7 [PubMed] Related Publications
MiRs was efficiently bound to water-soluble positively charged gold nanoparticles through complementary electrostatic interaction. MiR-122 has been considered to be specifically expressed in liver and involved in inducing hepatocyte apoptosis through bcl-w pathway, which could be efficiently bound to water dispersible positively charged gold nanoparticles and conjugated with folic acid (FA) to target specific cancer cells, through complementary electrostatic interaction. These gold nanoparticles-miR-122-FA nanocomplexes (GMN) were disrupted and miR-122 was released by glutathione (GSH) at intracellular concentrations. In contrast, there was almost no detectable miR-122 released from GMN by extracellular concentration of GSH. The formation of GMN and GSH-mediated miR-122 release from the complexes were corroborated by dye displacement assay, electrophoresis experiment and transmission electron microscopy (TEM). With FA funcition, the GMN can target to the HepG2 cell membrane efficiently revealed by scanning electron microscopy (SEM). The released miR-122 retained apoptosis-inducing activity after being transfected into HepG2 cells. The transfection efficiency measured by MTT assay and flow cytometry was comparable with the positive control. We determined the effects of GMN on HepG2 cells viability and apoptosis by using fluorescence light microscopy and SDS-PAGE/immunoblots. The obvious concentration gradient of GSH in nature between the intra- and extracellular environments as well as the GSH concentration-dependent release suggest that these positively charged gold nanoparticles can be used as a novel visible vehicle for gene delivery and open up promising opportunities for target applications in the future.

Peterson LF, Sun H, Liu Y, et al.
Targeting deubiquitinase activity with a novel small-molecule inhibitor as therapy for B-cell malignancies.
Blood. 2015; 125(23):3588-97 [PubMed] Related Publications
Usp9x was recently shown to be highly expressed in myeloma patients with short progression-free survival and is proposed to enhance stability of the survival protein Mcl-1. In this study, we found that the partially selective Usp9x deubiquitinase inhibitor WP1130 induced apoptosis and reduced Mcl-1 protein levels. However, short hairpin RNA-mediated knockdown (KD) of Usp9x in myeloma cells resulted in transient induction of apoptosis, followed by a sustained reduction in cell growth. A compensatory upregulation of Usp24, a deubiquitinase closely related to Usp9x, in Usp9x KD cells was noted. Direct Usp24 KD resulted in marked induction of myeloma cell death that was associated with a reduction of Mcl-1. Usp24 was found to sustain myeloma cell survival and Mcl-1 regulation in the absence of Usp9x. Both Usp9x and Usp24 were expressed and activated in primary myeloma cells whereas Usp24 protein overexpression was noted in some patients with drug-refractory myeloma and other B-cell malignancies. Furthermore, we improved the drug-like properties of WP1130 and demonstrated that the novel compound EOAI3402143 dose-dependently inhibited Usp9x and Usp24 activity, increased tumor cell apoptosis, and fully blocked or regressed myeloma tumors in mice. We conclude that small-molecule Usp9x/Usp24 inhibitors may have therapeutic activity in myeloma.

Faber AC, Farago AF, Costa C, et al.
Assessment of ABT-263 activity across a cancer cell line collection leads to a potent combination therapy for small-cell lung cancer.
Proc Natl Acad Sci U S A. 2015; 112(11):E1288-96 [PubMed] Article available free on PMC after 17/09/2015 Related Publications
BH3 mimetics such as ABT-263 induce apoptosis in a subset of cancer models. However, these drugs have shown limited clinical efficacy as single agents in small-cell lung cancer (SCLC) and other solid tumor malignancies, and rational combination strategies remain underexplored. To develop a novel therapeutic approach, we examined the efficacy of ABT-263 across >500 cancer cell lines, including 311 for which we had matched expression data for select genes. We found that high expression of the proapoptotic gene Bcl2-interacting mediator of cell death (BIM) predicts sensitivity to ABT-263. In particular, SCLC cell lines possessed greater BIM transcript levels than most other solid tumors and are among the most sensitive to ABT-263. However, a subset of relatively resistant SCLC cell lines has concomitant high expression of the antiapoptotic myeloid cell leukemia 1 (MCL-1). Whereas ABT-263 released BIM from complexes with BCL-2 and BCL-XL, high expression of MCL-1 sequestered BIM released from BCL-2 and BCL-XL, thereby abrogating apoptosis. We found that SCLCs were sensitized to ABT-263 via TORC1/2 inhibition, which led to reduced MCL-1 protein levels, thereby facilitating BIM-mediated apoptosis. AZD8055 and ABT-263 together induced marked apoptosis in vitro, as well as tumor regressions in multiple SCLC xenograft models. In a Tp53; Rb1 deletion genetically engineered mouse model of SCLC, the combination of ABT-263 and AZD8055 significantly repressed tumor growth and induced tumor regressions compared with either drug alone. Furthermore, in a SCLC patient-derived xenograft model that was resistant to ABT-263 alone, the addition of AZD8055 induced potent tumor regression. Therefore, addition of a TORC1/2 inhibitor offers a therapeutic strategy to markedly improve ABT-263 activity in SCLC.

Zhou M, Wang T, Lai H, et al.
Targeting of the deubiquitinase USP9X attenuates B-cell acute lymphoblastic leukemia cell survival and overcomes glucocorticoid resistance.
Biochem Biophys Res Commun. 2015; 459(2):333-9 [PubMed] Related Publications
Although previous studies attributed a pro-survival role to USP9X in human cancer, how USP9X affects B-cell acute lymphoblastic leukemia (B-ALL) remains unclear. Here, we found that USP9X is overexpressed in B-ALL cell lines and human patients. We investigated the role of USP9X in B-ALL and found that USP9X knockdown significantly reduced leukemic cell growth and increased spontaneous apoptosis, thereby improving survival in immunodeficient mice. These effects are partially mediated by the intrinsic apoptotic pathway, as we found that USP9X-knockdown leukemic cells displayed MCL1 down-regulation, with decreased BCL-2/BCL-XL levels and increased BAX levels. In addition, we demonstrated that USP9X inhibition negatively regulates mTORC1 activity toward its substrate S6K1. Clinically, USP9X inhibition sensitized glucocorticoid-resistant ALL cells to prednisolone; this observation reveals a potential avenue for improving the treatment of drug-resistant relapses. Collectively, our findings suggest that the combination of USP9X targeting and glucocorticoids treatment has attractive utility in B-ALL. This approach represents a potential strategy for promising combination therapies for lymphoid malignancies.

Ferreira AF, de Oliveira GL, Tognon R, et al.
Apoptosis-related gene expression profile in chronic myeloid leukemia patients after imatinib mesylate and dasatinib therapy.
Acta Haematol. 2015; 133(4):354-64 [PubMed] Related Publications
BACKGROUND/AIMS: We investigated the effects of tyrosine kinase inhibitors (TKIs) on the expression of apoptosis-related genes (BCL-2 and death receptor family members) in chronic myeloid leukemia (CML) patients.
METHODS: Peripheral blood mononuclear cells from 32 healthy subjects and 26 CML patients were evaluated before and after treatment with imatinib mesylate (IM) and dasatinib (DAS) by quantitative PCR.
RESULTS: Anti-apoptotic genes (c-FLIP and MCL-1) were overexpressed and the pro-apoptotic BIK was reduced in CML patients. Expression of BMF, A1, c-FLIP, MCL-1, CIAP-2 and CIAP-1 was modulated by DAS. In IM-resistant patients, expression of A1, c-FLIP, CIAP-1 and MCL-1 was upregulated, and BCL-2, CIAP-2, BAK, BAX, BIK and FASL expression was downregulated.
CONCLUSION: Taken together, our results point out that, in CML, DAS interferes with the apoptotic machinery regulation. In addition, the data suggest that apoptosis-related gene expression profiles are associated with primary resistance to IM.

Priedigkeit N, Wolfe N, Clark NL
Evolutionary signatures amongst disease genes permit novel methods for gene prioritization and construction of informative gene-based networks.
PLoS Genet. 2015; 11(2):e1004967 [PubMed] Article available free on PMC after 17/09/2015 Related Publications
Genes involved in the same function tend to have similar evolutionary histories, in that their rates of evolution covary over time. This coevolutionary signature, termed Evolutionary Rate Covariation (ERC), is calculated using only gene sequences from a set of closely related species and has demonstrated potential as a computational tool for inferring functional relationships between genes. To further define applications of ERC, we first established that roughly 55% of genetic diseases posses an ERC signature between their contributing genes. At a false discovery rate of 5% we report 40 such diseases including cancers, developmental disorders and mitochondrial diseases. Given these coevolutionary signatures between disease genes, we then assessed ERC's ability to prioritize known disease genes out of a list of unrelated candidates. We found that in the presence of an ERC signature, the true disease gene is effectively prioritized to the top 6% of candidates on average. We then apply this strategy to a melanoma-associated region on chromosome 1 and identify MCL1 as a potential causative gene. Furthermore, to gain global insight into disease mechanisms, we used ERC to predict molecular connections between 310 nominally distinct diseases. The resulting "disease map" network associates several diseases with related pathogenic mechanisms and unveils many novel relationships between clinically distinct diseases, such as between Hirschsprung's disease and melanoma. Taken together, these results demonstrate the utility of molecular evolution as a gene discovery platform and show that evolutionary signatures can be used to build informative gene-based networks.

Kempf W, Kazakov DV, Hübscher E, et al.
Cutaneous borreliosis associated with T cell-predominant infiltrates: a diagnostic challenge.
J Am Acad Dermatol. 2015; 72(4):683-9 [PubMed] Related Publications
BACKGROUND: With the exception of erythema migrans, Borrelia infection of the skin manifests much more commonly with B cell-rich infiltrates. T cell-rich lesions have rarely been described.
OBJECTIVE: We report a series of 6 patients with cutaneous borreliosis presenting with T cell-predominant skin infiltrates.
METHODS: We studied the clinicopathologic and molecular features of 6 patients with T cell-rich skin infiltrates.
RESULTS: Half of the patients had erythematous patchy, partly annular lesions, and the other patients had features of acrodermatitis chronica atrophicans. Histopathology revealed a dense, band-like or diffuse dermal infiltrate. Apart from small, well differentiated lymphocytes, there were medium-sized lymphocytes with slight nuclear atypia and focal epidermotropism. An interstitial histiocytic component was found in 4 cases, including histiocytic pseudorosettes. Fibrosis was present in all cases but varied in severity and distribution. In 5 patients, borrelia DNA was detected in lesional tissue using polymerase chain reaction studies. No monoclonal rearrangement of T-cell receptor gamma genes was found.
LIMITATIONS: This retrospective study was limited by the small number of patients.
CONCLUSION: In addition to unusual clinical presentation, cutaneous borreliosis can histopathologically manifest with a T cell-rich infiltrate mimicking cutaneous T-cell lymphoma. Awareness of this clinicopathologic constellation is important to prevent underrecognition of this rare and unusual presentation representing a Borrelia-associated T-cell pseudolymphoma.

Singh RK, Cho K, Padi SK, et al.
Mechanism of N-Acylthiourea-mediated activation of human histone deacetylase 8 (HDAC8) at molecular and cellular levels.
J Biol Chem. 2015; 290(10):6607-19 [PubMed] Article available free on PMC after 06/03/2016 Related Publications
We reported previously that an N-acylthiourea derivative (TM-2-51) serves as a potent and isozyme-selective activator for human histone deacetylase 8 (HDAC8). To probe the molecular mechanism of the enzyme activation, we performed a detailed account of the steady-state kinetics, thermodynamics, molecular modeling, and cell biology studies. The steady-state kinetic data revealed that TM-2-51 binds to HDAC8 at two sites in a positive cooperative manner. Isothermal titration calorimetric and molecular modeling data conformed to the two-site binding model of the enzyme-activator complex. We evaluated the efficacy of TM-2-51 on SH-SY5Y and BE(2)-C neuroblastoma cells, wherein the HDAC8 expression has been correlated with cellular malignancy. Whereas TM-2-51 selectively induced cell growth inhibition and apoptosis in SH-SY5Y cells, it showed no such effects in BE(2)-C cells, and this discriminatory feature appears to be encoded in the p53 genotype of the above cells. Our mechanistic and cellular studies on HDAC8 activation have the potential to provide insight into the development of novel anticancer drugs.

Wang YF, Liu B, Fan XS, et al.
Thyroid carcinoma showing thymus-like elements: a clinicopathologic, immunohistochemical, ultrastructural, and molecular analysis.
Am J Clin Pathol. 2015; 143(2):223-33 [PubMed] Related Publications
OBJECTIVES: To investigate the clinicopathologic, immunophenotypic, ultrastructural, and molecular features of thyroid carcinoma showing thymus-like elements (CASTLE).
METHODS: We retrospectively analyzed the clinicopathologic data of 10 patients with CASTLE and described the immunophenotypic and ultrastructural features of these tumors. The expression of Epstein-Barr virus-encoded RNA and the gene status of EGFR, C-KIT, and HER-2 were also assessed by molecular techniques.
RESULTS: The tumor cells were positive for CD5, CD117, p63, HMWK, EGFR, GLUT-1, Pax8, E-cadherin, bcl-2, and p53 in all cases and for CA-IX, CEA, p16, HER-2, and neuroendocrine markers in some cases. Ultrastructural examination indicated that the tumor cells contained large quantities of tonofilament with abundant intercellular desmosomes, including intracytoplasmic neuroendocrine granules in one case. EGFR gene amplification in two patients and polyploidy of chromosome 7 in one patient were identified by fluorescence in situ hybridization. Sequencing analysis revealed that a synonymous mutation, Q787Q 2363 (G→A), occurred on exon 20 of the EGFR gene in three patients.
CONCLUSIONS: GLUT-1 can be used as a novel biomarker for CASTLE, and combined detection of GLUT-1 with CD5 and CD117 aids in the diagnosis of this tumor. Aberrant expression of Bcl-2, p53, p16, E-cadherin, EGFR, C-KIT, and HER-2 may play important roles in the development of CASTLE.

Zhang MY, Churpek JE, Keel SB, et al.
Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy.
Nat Genet. 2015; 47(2):180-5 [PubMed] Related Publications
We report germline missense mutations in ETV6 segregating with the dominant transmission of thrombocytopenia and hematologic malignancy in three unrelated kindreds, defining a new hereditary syndrome featuring thrombocytopenia with susceptibility to diverse hematologic neoplasms. Two variants, p.Arg369Gln and p.Arg399Cys, reside in the highly conserved ETS DNA-binding domain. The third variant, p.Pro214Leu, lies within the internal linker domain, which regulates DNA binding. These three amino acid sites correspond to hotspots for recurrent somatic mutation in malignancies. Functional studies show that the mutations abrogate DNA binding, alter subcellular localization, decrease transcriptional repression in a dominant-negative fashion and impair hematopoiesis. These familial genetic studies identify a central role for ETV6 in hematopoiesis and malignant transformation. The identification of germline predisposition to cytopenias and cancer informs the diagnosis and medical management of at-risk individuals.

Kim J, Jeong D, Nam J, et al.
MicroRNA-124 regulates glucocorticoid sensitivity by targeting phosphodiesterase 4B in diffuse large B cell lymphoma.
Gene. 2015; 558(1):173-80 [PubMed] Related Publications
Glucocorticoids (GCs) are chemotherapeutic drugs commonly used to treat hematological malignancies. However, a significant fraction of patients develop resistance to GCs during treatment. A better insight into how GC resistance develops is therefore needed. It was previously shown that cyclic AMP (cAMP) induces sensitivity to GCs by inhibiting the AKT/mTOR/MCL1 signaling, while high levels of phosphodiesterase 4B (PDE4B) reverse the effect of cAMP on GC responses in B-cell lymphoma. Here, we show that miR-124 influences GC-induced apoptosis by directly targeting PDE4B. Stable expression of miR-124 in diffuse large B cell lymphoma (DLBCL) cell lines diminished PDE4B expression. This was associated with increased cAMP levels, inhibition of the AKT/mTOR/MCL1 survival pathway, upregulation of GRα expression, and improved sensitivity to GCs in the presence of forskolin, an activator of adenylyl cyclase. Interestingly, miR-124 did not affect GC sensitivity in the absence of forskolin, indicating that the effect of this miRNA is accomplished via downregulation of PDE4B expression. Further, restoration of PDE4B expression in miR-124 cells rescued the phenotypic effect of this miRNA, demonstrating the critical role of PDE4B in miR-124-mediated regulation of the GC response. Our study supports the notion that miR-124 could be an attractive therapeutic target for overcoming GC resistance in DLBCL.

Jin Y, Lu J, Wen J, et al.
Regulation of growth of human bladder cancer by miR-192.
Tumour Biol. 2015; 36(5):3791-7 [PubMed] Related Publications
The regulation of microRNA-192 (miR-192) is impaired in many cancers. Here, we investigated the role of miR-192 in the proliferation, cell cycle progression, and apoptosis of bladder cancer cells. Human bladder cancer cells were transfected with human miR-192 precursor or non-specific control miRNA. The effect of miR-192 on cell proliferation was assessed by a MTT assay. The effects of miR-192 on cell cycle regulation and apoptosis were evaluated by flow cytometry. Western blot was used to analyze the protein levels of cyclin D1, p21, p27, Bcl-2, Bax, and Mcl-1. We found that overexpression of miR-192 significantly decreased the proliferation of bladder cancer cells by 22 and 54 % at 48 and 72 h, respectively. MiR-192-overexpressing cells exhibited a significant increase in G0/G1 phase and a significant decrease in S phase compared to the control miRNA-transfected cells. Moreover, overexpression of miR-192 significantly induced apoptotic death in bladder cancer cells, increased the levels of p21, p27, and Bax, and decreased the levels of cyclin D1, Bcl-2, and Mcl-1. Taken together, these data suggest that miR-192 may be a suppressor for bladder cancer cells by cell cycle regulation.

Chubb D, Broderick P, Frampton M, et al.
Genetic diagnosis of high-penetrance susceptibility for colorectal cancer (CRC) is achievable for a high proportion of familial CRC by exome sequencing.
J Clin Oncol. 2015; 33(5):426-32 [PubMed] Related Publications
PURPOSE: Knowledge of the contribution of high-penetrance susceptibility to familial colorectal cancer (CRC) is relevant to the counseling, treatment, and surveillance of CRC patients and families.
PATIENTS AND METHODS: To quantify the impact of germline mutation to familial CRC, we sequenced the mismatch repair genes (MMR) APC, MUTYH, and SMAD4/BMPR1A in 626 early-onset familial CRC cases ascertained through a population-based United Kingdom national registry. In addition, we evaluated the contribution of mutations in the exonuclease domain (exodom) of POLE and POLD1 genes that have recently been reported to confer CRC risk.
RESULTS: Overall mutations (pathogenic, likely pathogenic) in MMR genes make the highest contribution to familial CRC (10.9%). Mutations in the other established CRC genes account for 3.3% of cases. POLE/POLD1 exodom mutations were identified in three patients with family histories consistent with dominant transmission of CRC. Collectively, mutations in the known genes account for 14.2% of familial CRC (89 of 626 cases; 95% CI = 11.5, 17.2).
CONCLUSION: A genetic diagnosis is feasible in a high proportion of familial CRC. Mainstreaming such analysis in clinical practice should enable the medical management of patients and their families to be optimized. Findings suggest CRC screening of POLE and POLD1 mutation carriers should be comparable to that afforded to those at risk of HNPCC. Although the risk of CRC associated with unexplained familial CRC is in general moderate, in some families the risk is substantive and likely to be the consequence of unidentified genes, as exemplified by POLE and POLD1. Our findings have utility in the design of genetic analyses to identify such novel CRC risk genes.

Sochalska M, Tuzlak S, Egle A, Villunger A
Lessons from gain- and loss-of-function models of pro-survival Bcl2 family proteins: implications for targeted therapy.
FEBS J. 2015; 282(5):834-49 [PubMed] Related Publications
Cell survival depends on the maintenance of mitochondrial integrity controlled by a well-balanced interplay between anti- and pro-apoptotic B cell lymphoma 2 (Bcl2) family members. Given their frequent deregulation in human pathologies, including autoimmunity and cancer, significant research efforts have increased our molecular understanding of how Bcl2 proteins control cell death. This has fostered the development of small non-peptidic compounds, so-called BH3-mimetics, that show excellent prospects of passing clinical trials and entering daily use for targeted therapy. Possible limitations in clinical application may, to a certain degree, be predicted from loss-of-function phenotypes gathered from studies using gene-modified mice that we attempt to summarize and discuss in this context.

Irie N, Weinberger L, Tang WW, et al.
SOX17 is a critical specifier of human primordial germ cell fate.
Cell. 2015; 160(1-2):253-68 [PubMed] Article available free on PMC after 06/03/2016 Related Publications
Specification of primordial germ cells (PGCs) marks the beginning of the totipotent state. However, without a tractable experimental model, the mechanism of human PGC (hPGC) specification remains unclear. Here, we demonstrate specification of hPGC-like cells (hPGCLCs) from germline competent pluripotent stem cells. The characteristics of hPGCLCs are consistent with the embryonic hPGCs and a germline seminoma that share a CD38 cell-surface marker, which collectively defines likely progression of the early human germline. Remarkably, SOX17 is the key regulator of hPGC-like fate, whereas BLIMP1 represses endodermal and other somatic genes during specification of hPGCLCs. Notable mechanistic differences between mouse and human PGC specification could be attributed to their divergent embryonic development and pluripotent states, which might affect other early cell-fate decisions. We have established a foundation for future studies on resetting of the epigenome in hPGCLCs and hPGCs for totipotency and the transmission of genetic and epigenetic information.

Musilova K, Mraz M
MicroRNAs in B-cell lymphomas: how a complex biology gets more complex.
Leukemia. 2015; 29(5):1004-17 [PubMed] Related Publications
MicroRNAs (miRNAs) represent important regulators of gene expression besides transcriptional control. miRNA regulation can be involved in the cell developmental fate decisions, but can also have more subtle roles in buffering stochastic fluctuations in gene expression. They participate in pathways fundamental to B-cell development like B-cell receptor (BCR) signalling, B-cell migration/adhesion, cell-cell interactions in immune niches, and the production and class-switching of immunoglobulins. miRNAs influence B-cell maturation, generation of pre-, marginal zone, follicular, B1, plasma and memory B cells. In this review, we discuss miRNAs with essential functions in malignant B-cell development (such as miR-150, miR-155, miR-21, miR-34a, miR-17-92 and miR-15-16). We also put these miRNAs in the context of normal B-cell differentiation, as this is intimately connected to neoplastic B-cell development. We review miRNAs' role in the most common B-cell malignancies, including chronic lymphocytic leukaemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and mantle cell lymphoma (MCL). We focus on miR-contribution to the regulation of important signalling pathways (such as NF-κB, PI3K/AKT and TGF-β), BCR signalling and its modulators (such as PTEN, SHIP-1, ZAP-70, GAB1 and BTK), anti- and pro-apoptotic proteins (such as BCL2, MCL1, TCL1, BIM, p53 and SIRT1) and transcription factors (such as MYC, MYB, PU.1, FOXP1 and BCL6). We also discuss the association of miRNAs' expression levels with the patients' survival and response to therapy, summarizing their potential use as predictive and prognostic markers. Importantly, the targeting of miRNAs (like use of anti-miR-155 or miR-34a mimic) could provide a novel therapeutic approach as evidenced by tumour regression in xenograft mouse models and initial promising data from clinical trials.

Sehgal AR, Konig H, Johnson DE, et al.
You eat what you are: autophagy inhibition as a therapeutic strategy in leukemia.
Leukemia. 2015; 29(3):517-25 [PubMed] Related Publications
A deeper understanding of the role of autophagy, literally 'self-eating', in normal and cancer cell biology has emerged over the last few years. Autophagy serves as a vehicle for cells to respond to various stressors including genomic, hypoxic and nutrient stress, and to oppose mechanisms of 'programmed' cell death. Here, we review not only mechanisms of cell death and cell survival but also the early successes in applying autophagy inhibition strategies in solid tumors using the only currently available clinical inhibitor, oral hydroxychloroquine. In acute leukemia, currently available chemotherapy drugs promote cell death and demonstrate clinical benefit, but relapse and subsequent chemotherapy resistance is common. Increasing preclinical data suggest that autophagy is active in leukemia as a means of promoting cell survival in response to chemotherapy. We propose coupling autophagy inhibition strategies with current cytotoxic chemotherapy and discuss synergistic combinations of available anti-leukemic therapies with autophagy inhibition. Furthermore, novel autophagy inhibitors are in development and promise to provide new therapeutic opportunities for patients with leukemia.

Tong ZG, Liu N, Song HS, et al.
Cytochalasin B inhibits the proliferation of human glioma U251 cells through cell cycle arrest and apoptosis.
Genet Mol Res. 2014; 13(4):10811-22 [PubMed] Related Publications
Cytochalasin B (CB) is known to inhibit a number of cancer types, but its effects on gliomas are unknown. We examined the in vitro effects of CB on the proliferation of human glioma U251 cells, as well as determined its mechanism of action. Cell proliferation was determined using CCK-8. The effect of CB on U251 cell morphology was observed under a transmission electron microscope. Cell cycle distribution was assessed using propidium iodine and Giemsa staining, and cell apoptosis was determined by annexin V-fluorescein isothiocyanate/propidium iodide. Cell cycle-related proteins were determined by Western blot. CB effectively inhibited U251 cell proliferation in a dose- and time-dependent manner. The 24, 48, 72, and 96 h IC50 values were 6.41 x 10(-2), 9.76 x 10(-4), 2.57 x 10(-5), and 2.08 x 10(-5) M, respectively. CB increased the proportion of cells in the G2/M phase in a dose-dependent manner, thus increasing the mitotic index and decreasing cdc2 and cyclin B1 protein levels. CB induced morphological changes in the cytoskeleton. Additionally, 10(-5) M CB induced apoptosis in 23.4 ± 0.5% of U251 cells (P < 0.05 vs control group). Caspase-3, -8, and -9 activities were increased after CB treatment. CB inhibited U251 glioma cell proliferation by damaging the microfilament structure. CB also induced glioma cell apoptosis, suggesting that it may be an effective therapeutic agent against gliomas.

Ishida M, Mikami S, Shinojima T, et al.
Activation of aryl hydrocarbon receptor promotes invasion of clear cell renal cell carcinoma and is associated with poor prognosis and cigarette smoke.
Int J Cancer. 2015; 137(2):299-310 [PubMed] Related Publications
Although exposure to environmental pollutants is one of the risk factors for renal cell carcinoma (RCC), its relationship with carcinogenesis and the progression of RCC remains unknown. The present study was designed to elucidate the role of the aryl hydrocarbon receptor (AhR), a major mediator of carcinogenesis caused by environmental pollutants, in the progression of RCC. The expression of AhR was investigated in 120 patients with RCC using immunohistochemistry, and its relationship with clinicopathological parameters and prognoses was statistically analyzed. RCC cell lines were exposed to indirubin or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), AhR ligands, to activate the AhR pathway, or were transfected with small interfering RNA (siRNA) for AhR. The expression of the AhR target genes CYP1A1 and CYP1B1, matrix metalloproteinases (MMPs), and invasion through Matrigel(TM) were then examined. AhR was predominantly expressed in the nuclei of high-grade clear cell RCC (ccRCC) and tumor-infiltrating lymphocytes (TILs), and its expression levels in cancer cells and TILs correlated with the pathological tumor stage and histological grade. A multivariate Cox analysis revealed that the strong expression of AhR in cancer cells was a significant and independent predictor of disease-specific survival. AhR ligands up-regulated the expression of AhR and CYPs and promoted invasion by up-regulating MMPs. Furthermore, siRNA for AhR down-regulated CYPs, and inhibited cancer cell invasion together with the down-regulation of MMPs. These results suggest that AhR regulates the invasion of ccRCC and may be involved in tumor immunity. Therefore, inhibiting the activation of AhR may represent a potentially attractive therapeutic target for ccRCC patients.

Modugno M, Banfi P, Gasparri F, et al.
Mcl-1 antagonism is a potential therapeutic strategy in a subset of solid cancers.
Exp Cell Res. 2015; 332(2):267-77 [PubMed] Related Publications
Cancer cell survival is frequently dependent on the elevated levels of members of the Bcl-2 family of prosurvival proteins that bind to and inactivate BH3-domain pro-apoptotic cellular proteins. Small molecules that inhibit the protein-protein interactions between prosurvival and proapoptotic Bcl-2 family members (so-called "BH3 mimetics") have a potential therapeutic value, as indicated by clinical findings obtained with ABT-263 (navitoclax), a Bcl-2/Bcl-xL antagonist, and more recently with GDC-0199/ABT-199, a more selective antagonist of Bcl-2. Here, we report study results of the functional role of the prosurvival protein Mcl-1 against a panel of solid cancer cell lines representative of different tumor types. We observed silencing of Mcl-1 expression by small interfering RNAs (siRNAs) significantly reduced viability and induced apoptosis in almost 30% of cell lines tested, including lung and breast adenocarcinoma, as well as glioblastoma derived lines. Most importantly, we provide a mechanistic basis for this sensitivity by showing antagonism of Mcl-1 function with specific BH3 peptides against isolated mitochondria induces Bak oligomerization and cytochrome c release, therefore demonstrating that mitochondria from Mcl-1-sensitive cells depend on Mcl-1 for their integrity and that antagonizing Mcl-1 function is sufficient to induce apoptosis. Thus, our results lend further support for considering Mcl-1 as a therapeutic target in a number of solid cancers and support the rationale for development of small molecule BH3-mimetics antagonists of this protein.

Davis AL, Qiao S, Lesson JL, et al.
The quinone methide aurin is a heat shock response inducer that causes proteotoxic stress and Noxa-dependent apoptosis in malignant melanoma cells.
J Biol Chem. 2015; 290(3):1623-38 [PubMed] Article available free on PMC after 16/01/2016 Related Publications
Pharmacological induction of proteotoxic stress is rapidly emerging as a promising strategy for cancer cell-directed chemotherapeutic intervention. Here, we describe the identification of a novel drug-like heat shock response inducer for the therapeutic induction of proteotoxic stress targeting malignant human melanoma cells. Screening a focused library of compounds containing redox-directed electrophilic pharmacophores employing the Stress & Toxicity PathwayFinder(TM) PCR Array technology as a discovery tool, a drug-like triphenylmethane-derivative (aurin; 4-[bis(p-hydroxyphenyl)methylene]-2,5-cyclohexadien-1-one) was identified as an experimental cell stress modulator that causes (i) heat shock factor transcriptional activation, (ii) up-regulation of heat shock response gene expression (HSPA6, HSPA1A, DNAJB4, HMOX1), (iii) early unfolded protein response signaling (phospho-PERK, phospho-eIF2α, CHOP (CCAAT/enhancer-binding protein homologous protein)), (iv) proteasome impairment with increased protein-ubiquitination, and (v) oxidative stress with glutathione depletion. Fluorescence polarization-based experiments revealed that aurin displays activity as a geldanamycin-competitive Hsp90α-antagonist, a finding further substantiated by molecular docking and ATPase inhibition analysis. Aurin exposure caused caspase-dependent cell death in a panel of human malignant melanoma cells (A375, G361, LOX-IMVI) but not in non-malignant human skin cells (Hs27 fibroblasts, HaCaT keratinocytes, primary melanocytes) undergoing the aurin-induced heat shock response without impairment of viability. Aurin-induced melanoma cell apoptosis depends on Noxa up-regulation as confirmed by siRNA rescue experiments demonstrating that siPMAIP1-based target down-regulation suppresses aurin-induced cell death. Taken together, our data suggest feasibility of apoptotic elimination of malignant melanoma cells using the quinone methide-derived heat shock response inducer aurin.

El-Khattouti A, Sheehan NT, Monico J, et al.
CD133⁺ melanoma subpopulation acquired resistance to caffeic acid phenethyl ester-induced apoptosis is attributed to the elevated expression of ABCB5: significance for melanoma treatment.
Cancer Lett. 2015; 357(1):83-104 [PubMed] Related Publications
According to the cancer stem-like cell (CSC) hypothesis, neoplastic clones are maintained by a small fraction of cells with stem cell properties. Also, melanoma resistance to chemo- and radiotherapy is thought to be attributed to melanoma stem-like cells (MSCs). Caffeic acid phenethyl ester (CAPE) is a bioactive molecule, whose antitumor activity is approved in different tumor types. CAPE induced both apoptosis and E2F1 expression in CD133(-), but not in CD133(+) melanoma subpopulations. The resistance of CD133(+) melanoma subpopulation is attributed to the enhanced drug efflux mediated by ATP-binding cassette sub-family B member 5 (ABCB5), since the knockdown of ABCB5 was found to sensitize CD133(+) cells to CAPE. CAPE-induced apoptosis is mediated by E2F1 as evidenced by the abrogation of apoptosis induced in response to the knockdown of E2F1. The functional analysis of E2F1 in CD133(+) melanoma subpopulation demonstrated the ability of E2F1 gene transfer to trigger apoptosis of CD133(+) cells and to enhance the activation of apoptosis signal-regulating kinase (ASK1), c-Jun N-terminal kinase and p38, and the DNA-binding activities of the transcription factors AP-1 and p53. Also, the induction of E2F1 expression was found to enhance the expression of the pro-apoptotic proteins Bax, Noxa and Puma, and to suppress the anti-apoptotic protein Mcl-1. Using specific pharmacological inhibitors we could demonstrate that E2F1 overcomes the chemo-resistance of MSCs/CD133(+) cells by a mechanism mediated by both mitochondrial dysregulation and ER-stress-dependent pathways. In conclusion, our data addresses the mechanisms of CAPE/E2F1-induced apoptosis of chemo-resistant CD133(+) melanoma subpopulation.

Zhao L, Liu W, Xiao J, Cao B
The role of exosomes and "exosomal shuttle microRNA" in tumorigenesis and drug resistance.
Cancer Lett. 2015; 356(2 Pt B):339-46 [PubMed] Related Publications
How are intracellular proteins and nucleic acids transported to the appropriate sites, and how do they function at the proper time? This problem has plagued scientists for a long time. The roles of vesicles, and nanovesicles called exosomes, as carriers were revealed in 2013. Many types of cells can release exosomes, particularly tumor cells. Tumor-derived (TD) exosomes are rich in proteins and nucleic acids derived from parental cells. With the activity of signal transmission, these exosomes can guide communication between cells and induce cancer-related disorders in many signaling pathways. TD-exosomes can be a source of tumor antigen to induce an anti-tumor immune response but can also suppress the immune system. TD-exosomes are especially rich in microRNAs (miRNAs), which are in various pathological and physiological states. Therefore, exosomal miRNA can serve as a new diagnostic marker for cancers. Moreover, miRNAs in exosomes can shuttle between cells to communicate and exchange genetic material. Thus, TD-exosomes can be used as targeted therapies. Cell-type specificity, stability and accessibility from body fluids make exosomes valuable candidates for tumor diagnosis and targeted treatment.

Wang J, Zhong M, Liu B, et al.
Expression and functional analysis of novel molecule - Latcripin-13 domain from Lentinula edodes C91-3 produced in prokaryotic expression system.
Gene. 2015; 555(2):469-75 [PubMed] Related Publications
The shiitake mushroom Lentinula edodes has health benefits and is used to treat various diseases due to its immunomodulatory and antineoplastic properties. In the present study, the Latcripin-13 domain, isolated from L. edodes, was expressed in Escherichia coli Rosetta-gami(DE3) in the form of inclusion bodies. The Latcripin-13 domain was purified by Ni-His affinity chromatography with high purity and refolded by urea gradient dialysis. The product showed biological activity in A549 cells, a human lung cancer cell line, by flow cytometry and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) method. The MTT assay and the flow cytometry results revealed that there was a great difference between the Latcripin-13 domain-treated group and the control group (p<0.05). Similarly, cell apoptosis observed by transmission electron microscopy (TEM) supported the flow cytometry results. This work demonstrated that the Latcripin-13 domain can induce apoptosis of A549 cells, which will bring new insights into the development of new antitumor drugs in the future.

Zhang R, Jin S, Rao W, et al.
OVA12, a novel tumor antigen, promotes cancer cell growth and inhibits 5-fluorouracil-induced apoptosis.
Cancer Lett. 2015; 357(1):141-51 [PubMed] Related Publications
To achieve a better understanding of mechanisms that underlie carcinogenesis and to identify novel target molecules for diagnosis and therapy of carcinoma, we previously identified 24 distinct gene clones by immunoscreening of a cDNA library derived from an ovarian cancer patient through SEREX analysis. Among these genes we focused on a novel gene termed OVA12 and which putatively encodes a 114-amino-acid protein. In the present study, we found that OVA12 was ubiquitously overexpressed in diverse human tumor cell lines. Interestingly, we noticed that overexpression of OVA12 promoted proliferation of cancer cells in vitro and accelerated tumor growth in nude mice as compared to controls. Conversely, specific downregulation of OVA12 inhibited tumor cell proliferation and tumor growth both in vitro and in vivo. Furthermore, OVA12 inhibited 5-FU-induced apoptosis through specific upregulation of Mcl-1 and survivin. These results demonstrate that OVA12 is able to promote tumor growth, suggesting that this antigen might be a new potential target for development of cancer therapy.

Babcook MA, Sramkoski RM, Fujioka H, et al.
Combination simvastatin and metformin induces G1-phase cell cycle arrest and Ripk1- and Ripk3-dependent necrosis in C4-2B osseous metastatic castration-resistant prostate cancer cells.
Cell Death Dis. 2014; 5:e1536 [PubMed] Article available free on PMC after 16/01/2016 Related Publications
Castration-resistant prostate cancer (CRPC) cells acquire resistance to chemotherapy and apoptosis, in part, due to enhanced aerobic glycolysis and biomass production, known as the Warburg effect. We previously demonstrated that combination simvastatin (SIM) and metformin (MET) ameliorates critical Warburg effect-related metabolic aberrations of C4-2B cells, synergistically and significantly decreases CRPC cell viability and metastatic properties, with minimal effect on normal prostate epithelial cells, and inhibits primary prostate tumor growth, metastasis, and biochemical failure in an orthotopic model of metastatic CRPC, more effectively than docetaxel chemotherapy. Several modes of cell death activated by individual treatment of SIM or MET have been reported; however, the cell death process induced by combination SIM and MET treatment in metastatic CRPC cells remains unknown. This must be determined prior to advancing combination SIM and MET to clinical trial for metastatic CRPC. Treatment of C4-2B cells with combination 4 μM SIM and 2 mM MET (SIM+MET) led to significant G1-phase cell cycle arrest and decrease in the percentage of DNA-replicating cells in the S-phase by 24 h; arrest was sustained throughout the 96-h treatment. SIM+MET treatment led to enhanced autophagic flux in C4-2B cells by 72-96 h, ascertained by increased LC3B-II (further enhanced with lysosomal inhibitor chloroquine) and reduced Sequestosome-1 protein expression, significantly increased percentage of acidic vesicular organelle-positive cells, and increased autophagic structure accumulation assessed by transmission electron microscopy. Chloroquine, however, could not rescue CRPC cell viability, eliminating autophagic cell death; rather, autophagy was upregulated by C4-2B cells in attempt to withstand chemotherapy. Instead, SIM+MET treatment led to Ripk1- and Ripk3-dependent necrosis by 48-96 h, determined by propidium iodide-Annexin V flow cytometry, increase in Ripk1 and Ripk3 protein expression, necrosome formation, HMGB-1 extracellular release, and necrotic induction and viability rescue with necrostatin-1 and Ripk3-targeting siRNA. The necrosis-inducing capacity of SIM+MET may make these drugs a highly-effective treatment for apoptosis- and chemotherapy-resistant metastatic CRPC cells.

Palve V, Mallick S, Ghaisas G, et al.
Overexpression of Mcl-1L splice variant is associated with poor prognosis and chemoresistance in oral cancers.
PLoS One. 2014; 9(11):e111927 [PubMed] Article available free on PMC after 16/01/2016 Related Publications
BACKGROUND: Altered expression of Mcl-1, an anti-apoptotic member of the Bcl-2 family, has been linked to the progression and outcome of a variety of malignancies. We have previously reported the overexpression of Mcl-1 protein in human oral cancers. The present study aimed to evaluate the clinicopathological significance of the expression of three known Mcl-1 isoforms in oral tumors and the effect of targeting Mcl-1L isoform on chemosensitivity of oral cancer cells.
METHODS: The expression of Mcl-1 isoforms- Mcl-1L, Mcl-1S & Mcl-1ES was analyzed in 130 paired oral tumors and 9 oral cell lines using quantitative real-time PCR & protein by western blotting. The Mcl-1 mRNA levels were correlated with clinicopathological parameters and outcome of oral cancer patients. The effect of Mcl-1L shRNA or Obatoclax (a small molecule Mcl-1 inhibitor), in combination with Cisplatin on chemosensitivity of oral cancer cells was also assessed.
RESULTS: Anti-apoptotic Mcl-1L was predominantly expressed, over low or undetectable pro-apoptotic Mcl-1S and Mcl-1ES isoforms. The Mcl-1L transcripts were significantly overexpressed in all cancer cell lines and in 64% oral tumors versus adjacent normals (P<0.02). In oral cancer patients, high Mcl-1L expression was significantly associated with node positivity (P = 0.021), advanced tumor size (P = 0.013) and poor overall survival (P = 0.002). Multivariate analysis indicated Mcl-1L to be an independent prognostic factor for oral cancers (P = 0.037). Mcl-1L shRNA knockdown or its inhibition by Obatoclax in combination with Cisplatin synergistically reduced viability and growth of oral cancer cells than either treatment alone.
CONCLUSION: Our studies suggest that overexpression of Mcl-1L is associated with poor prognosis and chemoresistance in oral cancers. Mcl-1L is an independent prognostic factor and a potential therapeutic target in oral cancers.

Wu H, Schiff DS, Lin Y, et al.
Ionizing radiation sensitizes breast cancer cells to Bcl-2 inhibitor, ABT-737, through regulating Mcl-1.
Radiat Res. 2014; 182(6):618-25 [PubMed] Related Publications
Breast-conserving surgery followed by radiation therapy has become the standard of care for early stage breast cancer. However, there are some patients that develop a local failure. We have previously shown that Bcl-2 overexpression was associated with an increased risk of local recurrence in patients with early stage breast cancer. The purpose of this study was to explore an approach to overcome radiation resistance by targeting pro-survival Bcl-2 family proteins in breast cancer cells. The breast cancer cell lines MCF-7, ZR-75-1 and MDA-MB231 were used in this study. siRNAs were employed to silence myeloid cell leukemia 1 (Mcl-1). A small molecule inhibitor of Bcl-2, ABT-737, was used to target anti-apoptotic Bcl-2 family proteins. Apoptosis was identified by FITC Annexin V, PI staining and Western blot analysis. The sensitivity to ionizing radiation and ABT-737 were measured by clonogenic assays. The effect of radiation and ABT-737 was also tested in a MCF-7 xenograft mouse model. Our data demonstrate that the combination of ABT-737 and radiation-induced apoptosis had an inhibitory effect on breast cancer cell proliferation. However, treatment with ABT-737 resulted in elevated Mcl-1 in breast cancer cell lines. Targeting Mcl-1 by siRNA sensitized MCF-7 cells to ABT-737. We revealed that radiation blunted Mcl-1 elevation induced by ABT-737, and that radiation downregulated Mcl-1 by promoting its degradation. Our results indicate that radiation and ABT-737 exert a synergistic effect on breast cancer cell lines through downregulating Mcl-1 and activating the bak-apoptotic pathway. These results support the combination of radiation and pro-survival Bcl-2 family inhibitor as a potential novel therapeutic strategy in the local-regional management of breast cancer.

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