Growth Factor-Antagonized Rexinoid Apoptosis Involves Permissive PPARγ/RXR Heterodimers to Activate the Intrinsic Death Pathway by NO

Growth factor (GF) deprivation and/or blocking of cognate signaling can induce apoptosis and is the basis of several cancer treatment paradigms. We observed that RXR agonists; (rexinoids) induce apoptosis of tumor cells when GF support is abrogated. This rexinoid apoptosis involves activation of both iNOS and eNOS by RXR-PPAR gamma and results in production of apoptogenic NO. IGF/EGF-induced IGF receptor 1-mediated MAP kinase blocks rexinoid apoptosis by RXR phosphorylation. Combining rexinoids with the MAPK inhibitor U0126 induced apoptosis in human cancer cells in vitro and ex vivo and blocked xenograft growth in vivo. Our results suggest a regulatory mechanism in which GF signaling antagonizes RXR-PPAR gamma-mediated default apoptosis; to sustain cell life.