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Experimental Therapeutics, Molecular Targets, and Chemical Biology |
1 Division of Oncology, Beth Israel Deaconess Medical Center and Harvard Medical School and 2 Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts
Requests for reprints: James W. Mier, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215. E-mail: jmier{at}bidmc.harvard.edu.
Mitogen-activated protein kinase (MAPK) is activated in the majority of melanomas, and its activity is essential for cell survival. In this report, we examined the effects of a novel raf inhibitor BAY 43-9006 on melanoma cell viability and intracellular signaling and found that it induces apoptosis through a caspase-independent mechanism. At concentrations that suppress extracellular signal-regulated kinase (ERK) phosphorylation, BAY 43-9006 dephosphorylates Bad on Ser75 and Ser99, activates Bak and Bax, and reduces the mitochondrial transmembrane potential. BAY 43-9006 (sorafenib) down-modulates the levels of Bcl-2 and Bcl-XL in a MAPK-independent manner in A2058 and SKMEL5 melanoma cells but not in the more resistant A375 cells. Of the three lines tested, only A375 cells were rescued from BAY 43-9006–induced apoptosis by knocking down Bad. BAY 43-9006 induced poly(ADP-ribose) polymerase cleavage and the mitochondrial release of cytochrome c and SMAC. However, the pan-caspase inhibitor Z-VAD-fmk had only a modest protective effect against the drug, suggesting that BAY 43-9006–induced apoptosis is largely caspase independent. BAY 43-9006 but not the MAP/ERK kinase inhibitors PD98059 or U0126 induced the nuclear translocation of apoptosis-inducing factor (AIF) in A2058 and SKMEL5 cells, and the introduction of a small interfering RNA (siRNA) for AIF partially protected these cells from BAY 43-9006–induced apoptosis. The AIF siRNA had little effect in A375 cells, in which drug-induced AIF release was negligible. These data indicate that in sensitive cell lines, BAY 43-9006–induced apoptosis is independent of Bad dephosphorylation and caspase activation and largely mediated through the nuclear translocation of AIF. (Cancer Res 2006; 66(3): 1611-9)
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