RNA silencing of Mcl-1 enhances ABT-737-mediated apoptosis in melanoma: role for a caspase-8-dependent pathway

• Published in: PloS one 2009-08, Vol.4 (8), p.e6651-e6651
• Main Authors: Keuling, Angela M, Felton, Kathleen E A, Parker, Arabesque A M, Akbari, Majid, Andrew, Susan E, Tron, Victor A
• Format: Article
• Language: English
• Subjects: Activation; Apoptosis; Apoptosis - drug effects; Bcl-2 protein; Bcl-x protein; Biphenyl Compounds - pharmacology; Cancer; Cancer therapies; Caspase; Caspase 8 - genetics; Caspase 8 - metabolism; Caspase-10; Caspase-8; Caspase-9; Cell Biology/Cellular Death and Stress Responses; Cell death; Cell Line, Tumor; Chemotherapy; Cytotoxicity; Dermatology/Skin Cancers, including Melanoma and Lymphoma; Drug dosages; Fibroblasts; Gene Knockdown Techniques; Genetics; Haplotypes; Humans; Leukemia; Lung cancer; Lymphoma; Mcl-1 protein; Melanoma; Melanoma - enzymology; Melanoma - genetics; Melanoma - pathology; Metastasis; Mortality; Myeloid Cell Leukemia Sequence 1 Protein; Nitrophenols - pharmacology; Non-Hodgkin's lymphomas; Oncology/Skin Cancers; Pathology; Piperazines - pharmacology; Polymorphism, Genetic; Proteins; Proto-Oncogene Proteins c-bcl-2 - genetics; Radiation therapy; Ribonucleic acid; RNA; RNA Interference; RNA-mediated interference; Sensitivity; Skin cancer; Solid tumors; Studies; Sulfonamides - pharmacology; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0006651

Malignant melanoma is resistant to almost all conventional forms of chemotherapy. Recent evidence suggests that anti-apoptotic proteins of the Bcl-2 family are overexpressed in melanoma and may contribute to melanoma's striking resistance to apoptosis. ABT-737, a small-molecule inhibitor of Bcl-2, Bcl-xl and Bcl-w, has demonstrated efficacy in several forms of leukemia, lymphoma as well as solid tumors. However, overexpression of Mcl-1, a frequent observance in melanoma, is known to confer ABT-737 resistance. Here we report that knockdown of Mcl-1 greatly reduces cell viability in combination with ABT-737 in six different melanoma cell lines. We demonstrate that the cytotoxic effect of this combination treatment is due to apoptotic cell death involving not only caspase-9 activation but also activation of caspase-8, caspase-10 and Bid, which are normally associated with the extrinsic pathway of apoptosis. Caspase-8 (and caspase-10) activation is abrogated by inhibition of caspase-9 but not by inhibitors of the death receptor pathways. Furthermore, while caspase-8/-10 activity is required for the full induction of cell death with treatment, the death receptor pathways are not. Finally, we demonstrate that basal levels of caspase-8 and Bid correlate with treatment sensitivity. Our findings suggest that the combination of ABT-737 and Mcl-1 knockdown represents a promising, new treatment strategy for malignant melanoma. We also report a death receptor-independent role for extrinsic pathway proteins in treatment response and suggest that caspase-8 and Bid may represent potential markers of treatment sensitivity.