Abstract
BackgroundMalignant 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.Methodology/Principal FindingsHere 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.Conclusions/SignificanceOur 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.
Highlights
Over the past 40 years, the incidence of melanoma has increased more rapidly than any other type of cancer [1]
Knockdown of Mcl-1 using Dicer-substrate small interfering RNA (siRNA) To examine the effects of Mcl-1 knockdown and ABT-737 on melanoma in vitro, we used six melanoma cell lines: Lox IMVI, Malme-3M, MeWo, SK-MEL-2, SK-MEL-5 and SK-MEL-28
Maximum knockdown is achieved at a dose of 10 nM Dicer-substrate siRNA (DsiRNA) (Figure 2B and data not shown)
Summary
Over the past 40 years, the incidence of melanoma has increased more rapidly than any other type of cancer [1]. Metastatic melanoma is usually incurable, with a 5-year survival rate less than 10% and a median survival time of 7.5 months after diagnosis [3]. Recent studies have suggested that the Bcl-2 family of apoptotic proteins plays a critical role in chemoresistance in melanoma [7]. 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. Overexpression of Mcl-1, a frequent observance in melanoma, is known to confer ABT-737 resistance
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