Abstract 4679: Integrin and FAK signaling regulate ARHI-induced autophagy

Abstract

Abstract Autophagy selectively degrades cellular proteins, protein aggregates and organelles, providing energy in a nutrient deprived environment. We have reported that re-expression of ARHI, a maternally imprinted Ras-related tumor suppressor gene that is down regulated in more than 60% of ovarian cancers, induces autophagy. Persistence for ARHI-induced autophagy for several days is lethal for ovarian cancer cells in culture. In xenografts, however, ARHI-induced autophagy does not kill ovarian cancer cells, but rather is required to maintain a dormant state in the absence of a vascular supply. When ARHI is downregulated in vivo, previously dormant xenografts grow promptly and outgrowth of cancers is inhibited by treatment of dormant cancer cells with chloroquine. Growth factors (IGF-1, IL-8, VEGF) and ECM components (fibronectin) in the cancer microenvironment can rescue ovarian cancer cells from ARHI-induced autophagic death in cell culture. Rescue was associated with partial reversal of ARHI-mediated inhibition of PI3K signaling and AKT and mTOR activity. Consequently, we have hypothesized that both autophagy and survival factors (IGF-1, fibronectin) are required to maintain dormancy, where autophagy provides energy for avascular xenografts and survival factors prevent autophagic death by partially reversing inhibition of PI3K signaling. Here, we show that re-expression of ARHI in SKOv3 ovarian cancer cells inhibited integrin β1 expression and decreased FAK activation, stimulated by fibronectin and growth factors (IGF-1). Consistent with the importance of ECM, addition of fibronectin, a receptor for αvβ1 integrin, induced FAK activity and diminished ARHI-induced autophagy; whereas addition of neutralizing antibody against integrin β1 decreased FAK and Akt activities, enhancing autophagy. Autophagy induced by ARHI is dramatically reduced in cells that overexpress FAK and knockdown of FAK by RNA interference enhances ARHI-induced autophagy in ovarian cancer cells cultured on fibronectin. Our results suggest that the ECM and growth factors in the tumor microenvironment function to coordinate the activities of integrin β1, FAK and Akt to regulate ARHI-mediated autophagy, contributing to the survival of dormant ovarian cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4679.