Dysregulated mTORC1 renders cells critically dependent on desaturated lipids for survival under tumor-like stress.

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 mammalian target of rapamycin complex 1 (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(-/-) (tuberous sclerosis complex 2(-/-)) cells deprived of serum lipids exhibit a magnified unfolded protein response (UPR) but fail to appropriately expand their endoplasmic reticulum (ER), leading to inositol-requiring protein-1 (IRE1)-dependent cell death that can be reversed by the addition of unsaturated lipids. UPR activation and apoptosis were also detected in Tsc2-deficient kidney tumors. Importantly, we observed this phenotype in multiple human cancer cell lines and suggest that cells committed to unregulated growth within ischemic tumor microenvironments are unable to balance lipid and protein synthesis due to a critical limitation in desaturated lipids.
Authors	Regina M Young, Daniel Ackerman, Zachary L Quinn, Anthony Mancuso, Michaela Gruber, Liping Liu, Dionysios N Giannoukos, Ekaterina Bobrovnikova-Marjon, J Alan Diehl, Brian Keith, M Celeste Simon
Journal	Genes & development (Genes Dev) Vol. 27 Issue 10 Pg. 1115-31 (May 15 2013) ISSN: 1549-5477 [Electronic] United States
PMID	23699409 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	Antigens, Polyomavirus Transforming Lipids Membrane Proteins Multiprotein Complexes Proteins TSC2 protein, human Tsc2 protein, mouse Tuberous Sclerosis Complex 2 Protein Tumor Suppressor Protein p53 Tumor Suppressor Proteins ERN2 protein, human Ern2 protein, mouse Mechanistic Target of Rapamycin Complex 1 Protein Serine-Threonine Kinases TOR Serine-Threonine Kinases Endoribonucleases Oxygen
Topics	Animals Antigens, Polyomavirus Transforming (metabolism) Autophagy (drug effects) Cell Death (drug effects) Cell Hypoxia Cell Line, Tumor Cell Survival (drug effects) Cell Transformation, Neoplastic Endoplasmic Reticulum Stress Endoribonucleases (deficiency, genetics) Energy Metabolism Fibroblasts (drug effects, metabolism, pathology) Humans Kidney Neoplasms (metabolism, pathology) Lipid Metabolism (drug effects) Lipids (biosynthesis, blood, chemistry, pharmacology) Mechanistic Target of Rapamycin Complex 1 Membrane Proteins (deficiency, genetics, metabolism) Mice Multiprotein Complexes Neoplasms (metabolism, pathology) Oxygen (metabolism, pharmacology) Protein Serine-Threonine Kinases (deficiency, genetics, metabolism) Proteins (metabolism) Serum TOR Serine-Threonine Kinases Tuberous Sclerosis Complex 2 Protein Tumor Microenvironment Tumor Suppressor Protein p53 (deficiency, genetics) Tumor Suppressor Proteins (deficiency, genetics) Unfolded Protein Response

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