Abstract SY18-01: Hypoxia, metabolism, and tumor progression

Abstract

Abstract Solid tumors exhibit heterogeneous microenvironments, often characterized by limiting concentrations of oxygen (O2), glucose, and other nutrients. How oncogenic mutations alter stress response pathways, metabolism, and cell survival in the face of these challenges is incompletely understood. Here we report that constitutive mTORC1 activity renders hypoxic cells dependent on exogenous desaturated lipids, as levels of de novo synthesized unsaturated fatty acids are reduced under low O2. Specifically, we demonstrate that hypoxic Tsc2-/- cells deprived of serum lipids undergo mTORC1-dependent apoptosis associated with elevated reactive oxygen species (ROS), a persistent unfolded protein response (UPR), and a failure to fully activate autophagy. Of note, UPR activation and cell death can be reversed by the addition of unsaturated fatty acids or ROS inhibitors. Our data suggest that cancer cells committed to unregulated growth within ischemic tumor microenvironments are unable to balance protein and lipid synthesis due to a critical limitation in desaturated fatty acids. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY18-01. doi:1538-7445.AM2012-SY18-01