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Sensitization to the mitochondrial pathway of apoptosis augments melanoma tumor cell responses to conventional chemotherapeutic regimens.

ABSTRACT: Metastatic malignant melanoma is highly resistant to chemotherapy, and the average survival rate is under 1 year. The only FDA-approved conventional chemotherapy (i.e., dacarbazine) targets melanoma tumor cells by inducing a form of cell death referred to as apoptosis. However, dacarbazine exhibits a response rate of ~5%, and combination chemotherapies consisting of cisplatin, vinblastine, and dacarbazine often offer little clinical advantage over dacarbazine alone. Apoptosis is governed by the BCL-2 family of proteins, which is comprised of anti-apoptotic and pro-apoptotic members. To determine if the anti-apoptotic BCL-2 repertoire established the cell death threshold and chemoresistance in melanoma, a novel treatment strategy was designed to inhibit the anti-apoptotic BCL-2 members with ABT-737. Using various melanoma model systems, we determined the affects of ABT-737 on sensitivity to dacarbazine-based regimens. Strikingly, ABT-737 re-sensitized melanoma cell lines to common chemotherapeutics leading to marked BIM-mediated apoptosis. Cellular features of the ABT-737 combination treatments were loss of proliferation, mitochondrial fragmentation, nuclear condensation, phosphatidylserine exposure, and decreased clonogenic survival. We also observed significant anti-tumor activity in an in vivo melanoma model system. Our data indicate that ABT-737 may be a beneficial adjuvant therapy to improve melanoma response rates when conventional chemotherapy is the only option.

SUBMITTER: Anvekar RA

PROVIDER: S-EPMC3542597 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Sensitization to the mitochondrial pathway of apoptosis augments melanoma tumor cell responses to conventional chemotherapeutic regimens.

Anvekar R A RA Asciolla J J JJ Lopez-Rivera E E Floros K V KV Izadmehr S S Elkholi R R Belbin G G Sikora A G AG Chipuk J E JE

Cell death & disease 20121115

Metastatic malignant melanoma is highly resistant to chemotherapy, and the average survival rate is under 1 year. The only FDA-approved conventional chemotherapy (i.e., dacarbazine) targets melanoma tumor cells by inducing a form of cell death referred to as apoptosis. However, dacarbazine exhibits a response rate of ~5%, and combination chemotherapies consisting of cisplatin, vinblastine, and dacarbazine often offer little clinical advantage over dacarbazine alone. Apoptosis is governed by the ...[more]

PMID: 23152056

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Project description:BackgroundSorafenib is the standard targeted drug used to treat hepatocellular carcinoma (HCC), but the therapeutic response between individuals varies markedly. Recently, cytokine-based immunotherapy has been a topic of intense discussion in the fight against cancer. The aim of this study was to explore whether cytokine IL-2 could augment the anti-tumour effects of sorafenib on HCC.MethodsHepG2 and Huh7 cells were co-treated with sorafenib and IL-2 in vitro, and cellular viability and death were analysed through the MTT assay, TUNEL staining, LDH release assay, and western blotting. Mitochondrial function was measured via ELISA, immunofluorescence, and western blotting. Pathway blockers were used to establish the role of the JNK-TAZ pathways in regulating cancer cell phenotypes.ResultsOur data demonstrated that sorafenib treatment increased the HCC apoptotic rate, repressed cell proliferation, and inhibited migratory responses, and these effects were enhanced by IL-2 supplementation. Mechanistically, the combination of IL-2 and sorafenib interrupted mitochondrial energy metabolism by downregulating mitochondrial respiratory proteins. In addition, IL-2 and sorafenib co-treatment promoted mitochondrial dysfunction, as evidenced by the decreased mitochondrial potential, elevated mitochondrial ROS production, increased leakage of mitochondrial pro-apoptotic factors, and activation of the mitochondrial death pathway. A molecular investigation revealed that mitochondrial fission was required for the IL-2/sorafenib-mediated mitochondrial dysfunction. Mitochondrial fission was triggered by sorafenib and was largely amplified by IL-2 supplementation. Finally, we found that IL-2/sorafenib regulated mitochondrial fission via the JNK-TAZ pathways; blockade of the JNK-TAZ pathways abrogated the inhibitory effects of L-2/sorafenib on cancer survival, growth and mobility.ConclusionsAltogether, these data strongly suggest that additional supplementation with IL-2 enhances the anti-tumour activity of sorafenib by promoting the JNK-TAZ-mitochondrial fission axis. This finding will pave the way for new treatment modalities to control HCC progression by optimizing sorafenib-based therapy.

Project description:BackgroundCancer cell viability is strongly modulated by the Hippo pathway, which includes mammalian STE20-like protein kinase 1 (Mst1) and yes-associated protein (Yap). Although the roles of Mst1 and Yap in thyroid carcinoma cell death have been fully addressed, no study has determined whether differential modification of Mst1 and Yap could further suppress thyroid carcinoma progression. The aim of our study was to explore the antiapoptotic effects exerted by combined Mst1 overexpression and Yap knockdown in thyroid carcinoma MDA-T32 cells in vitro.MethodsMst1 adenovirus and Yap shRNA were transfected into MDA-T32 cells to overexpress Mst1 and inhibit Yap, respectively. Cell viability and death were determined via an MTT assay, a TUNEL assay and western blotting. Mitochondrial function, mitochondrial fission and pathway studies were performed via western blotting and immunofluorescence.ResultsThe results of our study showed that combined Mst1 overexpression and Yap knockdown further augmented MDA-T32 cell death by mediating mitochondrial damage. In addition, cancer cell migration and proliferation were suppressed by combined Mst1 overexpression and Yap knockdown. At the molecular level, mitochondrial membrane potential, ATP production, respiratory function, and caspase-9-related apoptosis were activated by combined Mst1 overexpression and Yap knockdown. Further, we found that fatal mitochondrial fission was augmented by combined Mst1 overexpression and Yap knockdown in a manner dependent on the JNK-MIEF1 pathway. Inhibition of JNK-MIEF1 pathway activity abolished the proapoptotic effects exerted by Mst1/Yap on MDA-T32 cells.ConclusionsTaken together, our data suggest that Mst1 activation and Yap inhibition coordinate to augment thyroid cancer cell death by controlling the JNK-MIEF1-mitochondria pathway, suggesting that differential regulation of the core Hippo pathway components is potentially a novel therapeutic tool for the treatment of thyroid cancer.

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Sensitization to the mitochondrial pathway of apoptosis augments melanoma tumor cell responses to conventional chemotherapeutic regimens.

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Sensitization to the mitochondrial pathway of apoptosis augments melanoma tumor cell responses to conventional chemotherapeutic regimens.

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