Placzek WJ, Wei J, Kitada S et al.A survey of the anti-apoptotic Bcl-2 subfamily expression in cancer types provides a platform to predict the efficacy of Bcl-2 antagonists in cancer therapy. Cell Death Dis 1:e40

Sanford/Burnham Medical Research Institute, La Jolla, CA 92037, USA.
Cell Death & Disease (Impact Factor: 5.01). 05/2010; 1(5):e40. DOI: 10.1038/cddis.2010.18
Source: PubMed


We investigated the mRNA expression levels of all six antiapoptotic Bcl-2 subfamily members in 68 human cancer cell lines using qPCR techniques and measured the ability of known Bcl-2 inhibitors to induce cell death in 36 of the studied tumor cell lines. Our study reveals that Mcl-1 represents the anti-apoptotic Bcl-2 subfamily member with the highest mRNA levels in the lung, prostate, breast, ovarian, renal, and glioma cancer cell lines. In leukemia/lymphoma and melanoma cancer cell lines, Bcl-2 and Bfl-1 had the highest levels of mRNA, respectively. The observed correlation between the cell killing properties of known Bcl-2 inhibitors and the relative mRNA expression levels of anti-apoptotic Bcl-2 proteins provide critical insights into apoptosis-based anticancer strategies that target Bcl-2 proteins. Our data may explain current challenges of selective Bcl-2 inhibitors in the clinic, given that severe expression of Bcl-2 seems to be limited to leukemia cell lines. Furthermore, our data suggest that in most cancer types a strategy targeted to Mcl-1 inhibition, or combination of Bfl-1 and Mcl-1 inhibition for melanoma, may prove to be more successful than therapies targeting only Bcl-2.

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Available from: William Placzek, Feb 10, 2014
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    • "Besides to mainly localize in the mitochondrial membrane, Mcl-1 has also been found in the nucleus and the cytoplasm [7]. Mcl-1 is highly expressed in a variety of human tumor tissues, such as breast cancer, colon cancer, lung cancer, ovarian cancer, prostate cancer, kidney cancer, and liver cancer [8] [9]. Although overexpression of Mcl-1 does not directly promote the proliferation of tumor cells, its ability to suppress apoptosis plays a key role for cancer cell to protect against the apoptosis-inducing effect caused by toxic factors. "
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    ABSTRACT: Aim. To investigate the role of miR-26b and Mcl-1 in TRAIL-inducing cell death in hepatocellular carcinoma. Methods. The expression of miR-26b and Mcl-1 in HCC was detected by RT-qPCR and western blot. The regulation of Mcl-1 by miR-26b was determined by luciferase reporter assay. MTT and flow cytometry were employed to detect the cell viability and apoptosis. Results. miR-26b is commonly downregulated in HCC cell lines compared with the LO2 cell line. In contrast, the Mcl-1 expression is upregulated in HCC cell lines. Bioinformatic analysis identified a putative target site in the Mcl-1 mRNA for miR-26b and luciferase reporter assay showed that miR-26b directly targeted the 3′-UTR (3′-Untranslated Regions) of Mcl-1 mRNA. Transfection of miR-26b mimics suppressed Mcl-1 expression in HCC cells and sensitized the cancer cells to TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) cytotoxicity. In addition, transfection of HCC cells with Mcl-1 expression plasmid abolished the sensitization effect of miR-26b to TRAIL-inducing apoptosis. Conclusions. Our study showed that miR-26b was a negative regulator of Mcl-1 gene and sensitized TRAIL-inducing apoptosis in HCC cells, suggesting that the miR-26b-Mcl-1 pathway might be a novel target for the treatment of HCC.
    06/2015; 2015:1-9. DOI:10.1155/2015/572738
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    • "Many cancers feature overexpression of pro-survival members of the Bcl-2 family [24]. In follicular lymphoma, constitutive high level expression of Bcl-2 results from a translocation that brings it under the control of the immunoglobulin heavy chain enhancer [25] [26], but expression of Bcl-2 or its pro-survival relatives Bcl-x L and Mcl-1 is also elevated in other cancers [27]. Enhanced activity of pro-survival Bcl-2 family proteins contributes to oncogenesis and can also result in resistance to chemotherapy and poor clinical outcome. "
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    ABSTRACT: Chemotherapy and radiotherapy can cause permanent damage to the genomes of surviving cells, provoking severe side effects such as second malignancies in some cancer survivors. Drugs that mimic the activity of death ligands, or antagonise pro-survival proteins of the Bcl-2 or IAP families have yielded encouraging results in animal experiments and early phase clinical trials. Because these agents directly engage apoptosis pathways, rather than damaging DNA to indirectly provoke tumour cell death, we reasoned that they may offer another important advantage over conventional therapies: minimisation or elimination of side effects such as second cancers that result from mutation of surviving normal cells. Disappointingly, however, we previously found that concentrations of death receptor agonists like TRAIL that would be present in vivo in clinical settings provoked DNA damage in surviving cells. In this study, we used cell line model systems to investigate the mutagenic capacity of drugs from two other classes of direct apoptosis-inducing agents: the BH3-mimetic ABT-737 and the IAP antagonists LCL161 and AT-406. Encouragingly, our data suggest that IAP antagonists possess negligible genotoxic activity. Doses of ABT-737 that were required to damage DNA stimulated Bax/Bak-independent signalling and exceeded concentrations detected in the plasma of animals treated with this drug. These findings provide hope that cancer patients treated by BH3-mimetics or IAP antagonists may avoid mutation-related illnesses that afflict some cancer survivors treated with conventional DNA-damaging anti-cancer therapies. Copyright © 2015 Elsevier B.V. All rights reserved.
    04/2015; 777:23-32. DOI:10.1016/j.mrfmmm.2015.04.005
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    • "Such is the theory behind the combination of 2-DG and ABT-263, in that this treatment targets two independent weaknesses that are nearly ubiquitous among cancer cells: dependence on aerobic glycolysis and overexpression/dependence on an intracellular target (Fig. 7). It has been shown that the anti-apoptotic subfamily of BCL-2 proteins is overexpressed in a large amount of leukemia subtypes [Placzek et al., 2010; Lagadinou et al., 2013]. The combinatory therapy of 2- DG and ABT-263 has already proven effective in vitro and in vivo in many tumor-based malignancies [Yamaguchi et al., 2011], and we have now shown in the present study that this combination of therapeutics could also serve as an effective treatment option in leukemias. "
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    ABSTRACT: Cancer therapeutics has seen an emergence and re-emergence of two metabolic fields in recent years, those of bioactive sphingolipids and glycolytic metabolism. Anaerobic glycolysis and its implications in cancer have been at the forefront of cancer research for over 90 years. More recently, the role of sphingolipids in cancer cell metabolism has gained recognition, notably ceramide's essential role in programmed cell death and the role of the glucosylceramide synthase (GCS) in chemotherapeutic resistance. Despite this knowledge, a direct link between these two fields has yet to be definitively drawn. Herein, we show that in a model of highly glycolytic cells, generation of the glycosphingolipid (GSL) glucosylceramide (GlcCer) by GCS was elevated in response to increased glucose availability, while glucose deprivation diminished GSL levels. This effect was likely substrate dependent, independent of both GCS levels and activity. Conversely, leukemia cells with elevated GSLs showed a significant change in GCS activity, but no change in glucose uptake or GCS expression. In a leukemia cell line with elevated GlcCer, treatment with inhibitors of glycolysis or the pentose phosphate pathway (PPP) significantly decreased GlcCer levels. When combined with pre-clinical inhibitor ABT-263, this effect was augmented and production of pro-apoptotic sphingolipid ceramide increased. Taken together, we have shown that there exists a definitive link between glucose metabolism and GSL production, laying the groundwork for connecting two distinct yet essential metabolic fields in cancer research. Furthermore, we have proposed a novel combination therapeutic option targeting two metabolic vulnerabilities for the treatment of leukemia. J. Cell. Biochem. © 2014 Wiley Periodicals, Inc.
    Journal of Cellular Biochemistry 01/2015; 116(1). DOI:10.1002/jcb.24943 · 3.26 Impact Factor
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