miR-125a-5p inhibits cell proliferation and induces apoptosis in colon cancer via targeting BCL2, BCL2L12 and MCL1
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The present work aimed to probe into the effect of long non-coding RNA (lncRNA) LINC00152 on gastric cancer (GC) cells proliferation by regulating miR-193a-3p and its target gene MCL1. Transfected si-LINC00152 was used to down-regulate LINC00152, and cells proliferation was measured by the cell counting kit-8 (CCK-8) assay. Cell apoptosis and cell cycle were analyzed by flow cytometry (FCM). Besides, we also detected the potential functional effects of differential expression of LINC00152 in vivo using nude mouse xenograft model. We overexpressed and downexpressed miR-193a-3p to study the in vitro effect of miR-193a-3p on GC cells proliferation and vitality. And MCL1 was silenced by shRNA to investigate the effect of MCL1 on proliferation of GC cells. In this research, LINC00152 was proven to have a higher expression level in GC tissues than in the adjacent normal tissues. GC cells proliferation was inhibited after LINC00152 was down-regulated. LINC00152 inhibited the expression of miR-193a-3p, which negatively regulated MCL1. In addition, GC cells proliferation was inhibited by cell transfection with shRNA-MCL1, and enhanced by transfection with miR-193a-3p mimics. Our study suggested that LINC00152 was overexpressed in GC tissues, and it down-regulated miR-193a-3p to enhance MCL1 expression thereby promoting GC cells proliferation.
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MCL1 (myeloid cell leukemia sequence 1 [BCL2-related]) is an anti-apoptotic BCL2 family protein that is upregulated in several human cancers. In malignancies, overexpression of MCL1 promotes cell survival and confers chemotherapeutic resistance. MCL1 is also highly expressed in normal myocardium, but the functional importance of MCL1 in myocytes has not been explored. We recently discovered that MCL1 plays an essential role in myocardial homeostasis and autophagy. Here, we discuss how loss of MCL1 in the adult mouse heart leads to mitochondrial dysfunction, impaired autophagy and development of heart failure.
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Abstract Targeting anti-apoptotic BCL2 family proteins has become an attractive therapeutic strategy for many cancers, and the BCL2-selective inhibitor ABT-199 (venetoclax) has obtained clinical success. However, MCL1 can promote drug resistance and overall cancer cell survival. Thus, there is a critical need to develop an effective drug that antagonizes MCL1. However, most putative MCL1 inhibitors have been misclassified as they fail to directly inhibit MCL1 in cells, but rather induce the pro-apoptotic protein NOXA. We have investigated three putative MCL1 inhibitors: MIM1, UMI-77, and A-1210477. All three compounds were developed in cell-free assays and then found to be cytotoxic, and hence assumed to directly target MCL1 in cells. Here, we investigated whether these compounds directly inhibit MCL1 or inhibit MCL1 indirectly through the induction of NOXA. Both MIM1- and UMI-77-induced NOXA through the unfolded protein response pathway, and sensitized leukemia cells to ABT-199; this cytotoxicity was dependent on NOXA suggesting that these compounds do not directly target MCL1. A-1210477 was the only compound that did not induce NOXA, but it still sensitized cells to ABT-199. A-1210477 induced accumulation of MCL1 protein consistent with it binding and preventing MCL1 degradation. However, at concentrations used in several prior studies, A-1210477 also induced cytochrome c release, caspase activation, and apoptosis in a BAX/BAK-independent manner. Furthermore, the release of cytochrome c occurred without loss of mitochondrial membrane potential. This apoptosis was extremely rapid, sometimes occurring within 0.5–1 h. Hence, we have identified a novel mechanism of apoptosis that circumvents the known mechanisms of cytochrome c release. It remains to be determined whether these unexpected mechanisms of action of putative BH3 mimetics will have therapeutic potential.
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Abstract Myeloid cell leukemia 1 (MCL1) is a member of the BCL2 family of proteins governing the apoptosis pathway and is one of the most frequently amplified genes in cancer. MCL1 overexpression often results in dependence on MCL1 for survival and is linked to resistance to anticancer therapies. However, the development of direct MCL1 inhibitors has proven challenging and new modalities for targeting MCL1 are required. Alternative splicing of MCL1 converts the anti-apoptotic MCL1 long (MCL1L) isoform to the BH3-only MCL1 short (MCL1S) isoform, which has been reported to be pro-apoptotic. Thus, changing MCL1 isoform levels through modulation of RNA splicing may represent an attractive approach to targeting MCL1-amplified cancers. To this end, we tested a collection of small molecule SF3B modulators that impact RNA splicing on MCL1-dependent and MCL1-independent NSCLC cell lines. SF3B modulators induced rapid downregulation of the long form and upregulation of the short- and intron-containing form of MCL1 across models; however, apoptosis was only observed in MCL1-dependent cells. Importantly, SF3B modulators preferentially killed MCL1-dependent cell lines and sensitivity correlated with MCL1 amplification. To dissect the mechanism of SF3B modulator-induced cytotoxicity, we overexpressed either the cDNA for the BH3-only short isoform or the full length isoform of MCL1. Surprisingly, overexpression of MCL1S cDNA had no significant effect on cells by itself and did not sensitize cells to SF3B modulator cytotoxicity. Conversely, MCL1L-specific shRNA knockdown was sufficient to kill MCL1-dependent cells and SF3B modulator cytotoxicity was rescued by expression of MCL1L cDNA. Together, these results argue that MCL1L modulation and not MCL1S upregulation is the effector of SF3B modulator cytotoxicity. In immunocompromised mice bearing MCL1-dependent xenograft models, SF3B1 modulator treatment resulted in significant downregulation of MCL1 levels accompanied by induction of apoptosis and robust efficacy at well-tolerated doses. Moreover, MCL1L cDNA expression in MCL1-dependent models rescued apoptosis induced by SF3B1 modulator treatment. These studies provide proof-of-concept that splicing modulation is an effective strategy for targeting cancers dependent on MCL1. Citation Format: Daniel Aird, Ermira Pazolli, Craig Furman, Linda Lee, Kaiko Kunii, Eun Sun Park, Craig Karr, Betty Chan, Michelle Aicher, Silvia Buonamici, John Yuan Wang, Jacob Feala, Lihua Yu, Markus Warmuth, Peter Smith, Peter Fekkes, Ping Zhu, Baudouin Gerard, Yoshiharu Mizui, Laura Corson. Targeting MCL1-dependent cancers with SF3B splicing modulators. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C8.
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<div>Abstract<p><b>Purpose:</b> To investigate the roles of BCL2, MCL1, and BCL-XL in the survival of diffuse large B-cell lymphoma (DLBCL).</p><p><b>Experimental designs:</b> Immunohistochemical analysis of 105 primary DLBCL samples, and Western blot analysis of 18 DLBCL cell lines for the expression of BCL2, MCL1, and BCL-XL. Pharmacologic targeting of BCL2, MCL1, and BCL-XL with ABT-199, homoharringtonine (HHT), and ABT-737. Analysis of DLBCL clones with manipulated expressions of BCL2, MCL1, and BCL-XL. Immunoprecipitation of MCL1 complexes in selected DLBCL cell lines. Experimental therapy aimed at inhibition of BCL2 and MCL1 using ABT-199 and HHT, single agent, or in combination, <i>in vitro</i> and <i>in vivo</i> on primary cell-based murine xenograft models of DLBCL.</p><p><b>Results:</b> By the pharmacologic targeting of BCL2, MCL1, and BCL-XL, we demonstrated that DLBCL can be divided into BCL2-dependent and MCL1-dependent subgroups with a less pronounced role left for BCL-XL. Derived DLBCL clones with manipulated expressions of BCL2, MCL1, and BCL-XL, as well as the immunoprecipitation experiments, which analyzed MCL1 protein complexes, confirmed these findings at the molecular level. We demonstrated that concurrent inhibition of BCL2 and MCL1 with ABT-199 and HHT induced significant synthetic lethality in most BCL2-expressing DLBCL cell lines. The marked cytotoxic synergy between ABT-199 and HHT was also confirmed <i>in vivo</i> using primary cell-based murine xenograft models of DLBCL.</p><p><b>Conclusions:</b> As homoharringtonine is a clinically approved antileukemia drug, and ABT-199 is in advanced phases of diverse clinical trials, our data might have direct implications for novel concepts of early clinical trials in patients with aggressive DLBCL. <i>Clin Cancer Res; 22(5); 1138–49. ©2015 AACR</i>.</p></div>
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Antiapoptotic BCL2 family members have been implicated in the pathogenesis of acute myelogenous leukemia (AML), but the functional significance and relative importance of individual proteins (e.g., BCL2, BCL-XL, and myeloid cell leukemia 1 [MCL1]) remain poorly understood. Here, we examined the expression of BCL2, BCL-XL, and MCL1 in primary human hematopoietic subsets and leukemic blasts from AML patients and found that MCL1 transcripts were consistently expressed at high levels in all samples tested. Consistent with this, Mcl1 protein was also highly expressed in myeloid leukemic blasts in a mouse Myc-induced model of AML. We used this model to test the hypothesis that Mcl1 facilitates AML development by allowing myeloid progenitor cells to evade Myc-induced cell death. Indeed, activation of Myc for 7 days in vivo substantially increased myeloid lineage cell numbers, whereas hematopoietic stem, progenitor, and B-lineage cells were depleted. Furthermore, Mcl1 haploinsufficiency abrogated AML development. In addition, deletion of a single allele of Mcl1 from fully transformed AML cells substantially prolonged the survival of transplanted mice. Conversely, the rapid lethality of disease was restored by coexpression of Bcl2 and Myc in Mcl1-haploinsufficient cells. Together, these data demonstrate a critical and dose-dependent role for Mcl1 in AML pathogenesis in mice and suggest that MCL1 may be a promising therapeutic target in patients with de novo AML.
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<div>Abstract<p><b>Purpose:</b> To investigate the roles of BCL2, MCL1, and BCL-XL in the survival of diffuse large B-cell lymphoma (DLBCL).</p><p><b>Experimental designs:</b> Immunohistochemical analysis of 105 primary DLBCL samples, and Western blot analysis of 18 DLBCL cell lines for the expression of BCL2, MCL1, and BCL-XL. Pharmacologic targeting of BCL2, MCL1, and BCL-XL with ABT-199, homoharringtonine (HHT), and ABT-737. Analysis of DLBCL clones with manipulated expressions of BCL2, MCL1, and BCL-XL. Immunoprecipitation of MCL1 complexes in selected DLBCL cell lines. Experimental therapy aimed at inhibition of BCL2 and MCL1 using ABT-199 and HHT, single agent, or in combination, <i>in vitro</i> and <i>in vivo</i> on primary cell-based murine xenograft models of DLBCL.</p><p><b>Results:</b> By the pharmacologic targeting of BCL2, MCL1, and BCL-XL, we demonstrated that DLBCL can be divided into BCL2-dependent and MCL1-dependent subgroups with a less pronounced role left for BCL-XL. Derived DLBCL clones with manipulated expressions of BCL2, MCL1, and BCL-XL, as well as the immunoprecipitation experiments, which analyzed MCL1 protein complexes, confirmed these findings at the molecular level. We demonstrated that concurrent inhibition of BCL2 and MCL1 with ABT-199 and HHT induced significant synthetic lethality in most BCL2-expressing DLBCL cell lines. The marked cytotoxic synergy between ABT-199 and HHT was also confirmed <i>in vivo</i> using primary cell-based murine xenograft models of DLBCL.</p><p><b>Conclusions:</b> As homoharringtonine is a clinically approved antileukemia drug, and ABT-199 is in advanced phases of diverse clinical trials, our data might have direct implications for novel concepts of early clinical trials in patients with aggressive DLBCL. <i>Clin Cancer Res; 22(5); 1138–49. ©2015 AACR</i>.</p></div>
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The prosurvival BCL2 family member MCL1 is frequently dysregulated in cancer. To overcome the significant challenges associated with inhibition of MCL1 protein-protein interactions, we rigorously applied small-molecule conformational restriction, which culminated in the discovery of AMG 176, the first selective MCL1 inhibitor to be studied in humans. We demonstrate that MCL1 inhibition induces a rapid and committed step toward apoptosis in subsets of hematologic cancer cell lines, tumor xenograft models, and primary patient samples. With the use of a human MCL1 knock-in mouse, we demonstrate that MCL1 inhibition at active doses of AMG 176 is tolerated and correlates with clear pharmacodynamic effects, demonstrated by reductions in B cells, monocytes, and neutrophils. Furthermore, the combination of AMG 176 and venetoclax is synergistic in acute myeloid leukemia (AML) tumor models and in primary patient samples at tolerated doses. These results highlight the therapeutic promise of AMG 176 and the potential for combinations with other BH3 mimetics. SIGNIFICANCE: AMG 176 is a potent, selective, and orally bioavailable MCL1 inhibitor that induces a rapid commitment to apoptosis in models of hematologic malignancies. The synergistic combination of AMG 176 and venetoclax demonstrates robust activity in models of AML at tolerated doses, highlighting the promise of BH3-mimetic combinations in hematologic cancers.See related commentary by Leber et al., p. 1511.This article is highlighted in the In This Issue feature, p. 1494.
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Abstract Dysregulated apoptotic mechanisms are central to the pathogenesis and maintenance of cancer, and are major barriers to effective treatment. The BCL2 gene family, comprised of both pro- and anti-apoptotic members, controls the intrinsic activation of apoptosis. Amplification of one of the anti-apoptotic members of this pathway, MCL1, constitutes one of the most frequent somatic genetic events in cancer. However, the design of small molecules targeting MCL1 has proven difficult, and the genomic determinants of MCL1 dependence are not well-understood. Furthermore, the contribution of MCL1 regulation in current chemotherapy drug action remains undefined. We therefore developed a chemical genomic approach to identify repressors of MCL1. We measured gene expression levels of all BCL2 family members upon treatment with 2,922 small molecules, including the majority of FDA-approved drugs. We indentified several small molecules inhibiting MCL1 expression, including a few widely used chemotherapy drugs and a natural product triptolide. Those compounds all share similar apoptotic profile when they were tested in panels of cell lines. Genomic profiling indicated that those compounds were global transcriptional repressors (TR). Nevertheless, MCL1 was among the most repressed genes. To further define the contribution of MCL1 repression by those TR compounds, we compared the sensitivity to TRs and MCL1 knockdown. Sensitivity to all TRs correlated with sensitivity to MCL1 knockdown by shRNA; and there is no additive effect of TRs and MCL1 shRNAs. Furthermore, ectopic expression of physiological levels of MCL1 rescued cells from TRs. Triptolide was able to inhibit tumor growth and promote survival in a mouse xenograft model that is sensitive to TR in vitro. Whole genome expression analysis revealed genomic features that correlated with sensitivity to these compounds and to MCL1 shRNAs, and may shed light on biomarker selection when targeting MCL1. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 13. doi:10.1158/1538-7445.AM2011-13
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