A Induction by FoxO3a Mediates the Anticancer ivities of the Broad-Range Kinase

ownload st targeted anticancer drugs are inhibitors of kinases that are aberrantly activated in cancer cells. Howhe mechanisms by which kinase inhibitors suppress tumor growth remain unclear. In this study, und that UCN-01, a staurosporine analogue and broad-range kinase inhibitor used in clinical trials, ts colon cancer cell growth by inducing apoptosis via PUMA, a BH3-only Bcl-2 family member and target. PUMA expression was markedly elevated in a p53-independent fashion following UCN-01 ent. The induction of PUMA by UCN-01 was mediated by direct binding of FoxO3a to the PUMA ter following inhibition of AKT signaling. Deficiency in PUMA abrogated UCN-01–induced apoptosis, e activation, and mitochondrial dysfunction, and rendered UCN-01 resistance in a clonogenic assay, as elevated PUMA expression or a BH3 mimetic sensitized UCN-01 induced apoptosis. Chemosenion by UCN-01 seemed to involve simultaneous PUMA induction through both p53-dependent and dependent mechanisms. Furthermore, deficiency in PUMA suppressed the antitumor effects of 01 in a xenograft model, concurrent with reduced apoptosis and caspase activation in vivo. These results st that PUMA-mediated apoptosis is pivotal for the anticancer activities of UCN-01, and possibly other sugge clinically used kinase inhibitor drugs, and that PUMA manipulation may be useful for improving their anticancer activities. Mol Cancer Ther; 9(11); OF1–10. ©2010 AACR.