Exon Skipping in Mcl-1 Results in a Bcl-2 Homology Domain 3 Only Gene Product That Promotes Cell Death

Bingle, Colin D.; Craig, Ruth W.; Swales, Brenka M.; Singleton, Vanessa; Zhou, Ping; Whyte, Moira K. B.

doi:10.1074/jbc.m909572199

Cited by 168 publications

(131 citation statements)

References 57 publications

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“…Accordingly, we show here that Mcl-1L accumulates in NSCLC cells following bortezomib treatment, which is consistent with published reports (27,28). Recently, shorter Mcl-1 splice variants (Mcl-1S) have been identified (42,43). These variants retain the PEST and BH3 domains but lack the COOH-terminal domains, generating proapoptotic BH3-only proteins.…”

Section: Discussionsupporting

confidence: 79%

Mapatumumab and lexatumumab induce apoptosis in TRAIL-R1 and TRAIL-R2 antibody-resistant NSCLC cell lines when treated in combination with bortezomib

Luster¹,

Carrell

McCormick³

et al. 2009

Molecular Cancer Therapeutics

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Mapatumumab and lexatumumab are fully human monoclonal antibodies that bind and activate human tumor necrosis factor-related apoptosis-inducing ligand receptors 1 and 2, respectively. These antibodies induce apoptosis in various tumor cell types, although the degree of sensitivity can vary from highly sensitive to completely resistant. Importantly, tumor cells that are partially or completely resistant to mapatumumab or lexatumumab can often be sensitized when treated in combination with chemotherapeutic drugs. In this regard, the proteasome inhibitor bortezomib has recently shown synergistic activity against established lymphoma cell lines and primary lymphomas when combined with mapatumumab and lexatumumab. Here, we report similar findings using a panel of human non-small cell lung cancer (NSCLC) cell lines. Specifically, we show that bortezomib rapidly induces sensitivity to mapatumumab and lexatumumab in NSCLC cell lines that are completely resistant to antibody alone and that bortezomib concentrations as low as 25 nmol/L sensitize NSCLC cells to the antibodies. Furthermore, bortezomib at the tested concentration has minimal effect on its own, indicating the combination generates synergistic cytotoxicity. Combination treatment induces activation of the caspase cascade and the effect of the combination is caspase dependent. Bortezomib treatment increases the intracellular levels of several important apoptosis regulators that may mediate enhanced sensitivity to mapatumumab and lexatumumab. These results suggest future evaluation of mapatumumab or lexatumumab in combination with bortezomib is warranted in NSCLC patients.

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Section: Discussionsupporting

confidence: 79%

Mapatumumab and lexatumumab induce apoptosis in TRAIL-R1 and TRAIL-R2 antibody-resistant NSCLC cell lines when treated in combination with bortezomib

Luster¹,

Carrell

McCormick³

et al. 2009

Molecular Cancer Therapeutics

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“…Previously, two alternative splicing variants of the human MCL-1 gene, MCL-1L and MCL-1S, were identified [4][5][6]. Exons I-III of MCL-1 encode the pro-survival MCL-1L protein, but splicing out exon II produces the cell deathinducing protein MCL-1S [5].…”

Section: Introductionmentioning

confidence: 99%

MCL‐1ES, a novel variant of MCL‐1, associates with MCL‐1L and induces mitochondrial cell death

Kim

Sim

et al. 2009

FEBS Letters

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Edited by Barry Halliwell Keywords:Myeloid cell leukemia-1 MCL-1L MCL-1 extra short BCL-2 family Apoptosis Splicing variant a b s t r a c t Myeloid cell leukemia-1 (MCL-1L) is a pro-survival member of the BCL-2 family that promotes cell survival. In this study, we identify a new splicing variant of human MCL-1 that encodes MCL-1ES (extra short). Sequence analysis indicates that this variant results from splicing within the first coding exon of MCL-1 at a non-canonical GC-AG donor-acceptor pair. The deduced sequence of MCL-1ES encodes a protein of 197 amino acids, and the PEST (proline, glutamic acid, serine, and threonine) motifs present in MCL-1L are absent. MCL-1ES interacts with MCL-1L and induces mitochondrial cell death, suggesting that alternative splicing of MCL-1 may control the fate of cells.

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“…7B). 42,43 In addition, belinostat up-regulated expression of the BH3-only apoptotic activator, BIM about 2-3-fold. Vincristine treatment had little effect on expression of either MCL-1 or BIM.…”

Section: Belinostat Curtails Vincristine-induced Sac Activation and Cmentioning

confidence: 99%

Belinostat and vincristine demonstrate mutually synergistic cytotoxicity associated with mitotic arrest and inhibition of polyploidy in a preclinical model of aggressive diffuse large B cell lymphoma

Havas

Rodrigues

Bhakta

et al. 2016

Cancer Biology & Therapy

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Diffuse Large B-cell lymphoma (DLBCL) is an aggressive malignancy that has a 60 percent 5-year survival rate, highlighting a need for new therapeutic approaches. Histone deacetylase inhibitors (HDACi) are novel therapeutics being clinically-evaluated in combination with a variety of other drugs. However, rational selection of companion therapeutics for HDACi is difficult due to their poorly-understood, celltype specific mechanisms of action. To address this, we developed a pre-clinical model system of sensitivity and resistance to the HDACi belinostat using DLBCL cell lines. In the current study, we demonstrate that cell lines sensitive to the cytotoxic effects of HDACi undergo early mitotic arrest prior to apoptosis. In contrast, HDACi-resistant cell lines complete mitosis after a short delay and arrest in G1. To force mitotic arrest in HDACi-resistant cell lines, we used low dose vincristine or paclitaxel in combination with belinostat and observed synergistic cytotoxicity. Belinostat curtails vincristine-induced mitotic arrest and triggers a strong apoptotic response associated with downregulated MCL-1 expression and upregulated BIM expression. Resistance to microtubule targeting agents (MTAs) has been associated with their propensity to induce polyploidy and thereby increase the probability of genomic instability that enables cancer progression. Co-treatment with belinostat effectively eliminated a vincristine-induced, actively cycling polyploid cell population. Our study demonstrates that vincristine sensitizes DLBCL cells to the cytotoxic effects of belinostat and that belinostat prevents polyploidy that could cause vincristine resistance. Our findings provide a rationale for using low dose MTAs in conjunction with HDACi as a potential therapeutic strategy for treatment of aggressive DLBCL.

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Exon Skipping in Mcl-1 Results in a Bcl-2 Homology Domain 3 Only Gene Product That Promotes Cell Death

Abstract: Mcl-1 is a member of the

Cited by 168 publications

References 57 publications

Mapatumumab and lexatumumab induce apoptosis in TRAIL-R1 and TRAIL-R2 antibody-resistant NSCLC cell lines when treated in combination with bortezomib

Mapatumumab and lexatumumab induce apoptosis in TRAIL-R1 and TRAIL-R2 antibody-resistant NSCLC cell lines when treated in combination with bortezomib

MCL‐1ES, a novel variant of MCL‐1, associates with MCL‐1L and induces mitochondrial cell death

Belinostat and vincristine demonstrate mutually synergistic cytotoxicity associated with mitotic arrest and inhibition of polyploidy in a preclinical model of aggressive diffuse large B cell lymphoma

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