Abstract 3779: ARHI-induced autophagy is mediated through activation of FoxO3a and induction of its target genes to promote the formation of autophagic complexes

The role of autophagy in oncogenesis remains ambiguous and the mechanisms that induce autophagy and regulate its outcome in human cancer are poorly understood. ARHI (DIRAS3), a Ras-related tumor suppressor, is downregulated in >60% of ovarian cancers. Re-expression of ARHI in ovarian cancer cells induces autophagy in culture and in xenografts, by blocking Ras activation and inhibiting PI3 kinase activity. ARHI also participates directly in the formation of autophagosomes by upregulating Atg4 and co-localizing with processed LC-3 II. Here we show that inhibition of PI3 kinase/Akt signaling and Ras activation by ARHI is mediated, in part, by down regulation of EGFR expression and EGFR phosphorylation. Inhibition of these signaling pathways reduced phosphorylation of FoxO3a and enhanced nuclear accumulation of FoxO3a transcription factor, resulting in increased transcription of Atg4, MAP-LC-3, and PUMA. Knockdown of FoxO3a by siRNA reduced ARHI- and rapamycin-induced autophagy. Whereas ARHI inhibits Class I PI3K activity, its expression induces Class III PI3K activity and contributes to the enhanced autophagy. Thus, ARHI-induced autophagy is through activation of the transcription factor FoxO3a, which increases the expression of several autophagy-related genes that contribute to the formation of the autophagic complexes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3779. doi:10.1158/1538-7445.AM2011-3779