The Bcl-2 family of proteins are the central regulators of mitochondriamediated apoptosis, which is engaged by the selective activation or induction of the proximal BH3-only members in response to distinct as well as overlapping signals. The BH3-only protein PUMA plays an essential role in p53-dependent and – independent apoptosis in human cancer cells and mice, and activates the mitochondrial pathway via the Bcl-2 family member Bax/Bak following neutralizing all members of antiapoptotic Bcl-2 like molecules. DNA damage induced by gammairradiation or commonly used chemotherapeutic agents such as 5- fluorouracil, adriamycin and etoposide, induce p53- dependent induction of PUMA and apoptosis. Nongenotoxic stresses such as growth factor deprivation, endoplasmic reticulum poisons and a number of kinase inhibitors induce PUMA through a number of other transcription factors including p73, NF-kB and FoxO3a. In the current study, we demonstrated that sunitinib induces PUMA expression independent of p53 in colon cancer cells. The induction of PUMA was mediated by the transcription factor FoxO3a upon inhibition of AKT. PUMA deficiency led to resistance to 18A sunitinib-induced apoptosis in cells as well as in xenografts. Our study provides a molecular mechanism of apoptosis induced by this non-selective kinase inhibitor in colon cancer cells, and has important implications for biomarker discovery and potential strategies to overcome resistance. Emerging evidence suggests that induction of apoptosis is an important mechanism of a wide variety of anticancer agents. Evasion of cell death is a hallmark of cancer and an important contributor to therapeutic resistance. In addition to well-documented effects of sunitinib in inhibiting tumor angiogenesis, our work demonstrates that sunitinib exhibits a strong pro-apoptotic activity in colon cancer cells via PUMA induction through transcription factor FoxO3a, but not p53, NF-kB p65 or p53 homologue p73 and p63. Sunitinibinduced apoptosis is associated with the induction of Bim or down regulation of Mcl-l in some colon cancer cell lines we tested. Earlier work demonstrated the involvement of Bim and STAT3 during sunitinib-induced apoptosis in other cells types. Together, these data suggest that induction of BH3-only proteins might be a 3PO common mechanism underlying sunitinib-induced cancer cell killing that might be affected by status of various kinases, and different BH3-only proteins might be important in different cells types. A number of more selective VEGFR inhibitors were also found to induce PUMA and apoptosis in colon cancer cells, supporting a non-angiogenic role of anti-VEGFR therapies.