Abstract 1000: Tyrosine kinase receptor EGFR regulates the switch between cell survival and cell death induced by autophagy under hypoxia in cancer cells

Abstract

Abstract Autophagy is an intracellular lysosomal degradation pathway characterized by the formation of autophagosomes. The primary function of autophagy is to allow cells to survive under stressful conditions. Autophagy is, however, a double-edge sword that can either promote cell survival or cell death. In cancer, hypoxia regions contribute to poor prognosis due to the ability of cancer cells to adapt to hypoxia in part through autophagy. In contrast, we have previously demonstrated that autophagy contributes to hypoxia induced cell death in cancer cells. In this study, we demonstrated that autophagy flux increased under hypoxia over time. At 4 hours of hypoxia, autophagy promoted cell survival whereas, at 48 hours of hypoxia, autophagy increased cell death. Furthermore, we found that the tyrosine phosphorylation of epidermal growth factor receptor (EGFR) increased at 4 hours and decreased at later times. This correlated with the ability of EGFR to bind with Beclin-1 at 4 hours but not 48 hours under hypoxia. Knocking down or inhibiting EGFR resulted in increased autophagy and cell death under hypoxia. In contrast, when EGFR was re-activated by the addition of EGF, the level of autophagy was reduced and amount of cell death decreased. Hypoxia led to autophagic excessive degradation of the lipid raft protein caveolin-1 (CAV1) that is known to bind to EGFR and activate EGFR in a ligand-independent manner under hypoxia. By knocking down CAV1, the amount of EGFR phosphorylation was increased under hypoxia and amount of autophagy and cell death decreased. This indicates that the activation of EGFR plays a critical role in the switch between cell survival and cell death induced by autophagy under hypoxia. Citation Format: Spencer B. Gibson, Yongqiang Chen, Elizabeth S. Henson, Daniel Huang. Tyrosine kinase receptor EGFR regulates the switch between cell survival and cell death induced by autophagy under hypoxia in cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1000. doi:10.1158/1538-7445.AM2015-1000