title: 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.affiliation: Abramson Family Cancer Research Institute.
authors.forename: Regina M
authors.initials: RM
authors.lastname: Young
authors.forename: Daniel
authors.initials: D
authors.lastname: Ackerman
authors.forename: Zachary L
authors.initials: ZL
authors.lastname: Quinn
authors.forename: Anthony
authors.initials: A
authors.lastname: Mancuso
authors.forename: Michaela
authors.initials: M
authors.lastname: Gruber
authors.forename: Liping
authors.initials: L
authors.lastname: Liu
authors.forename: Dionysios N
authors.initials: DN
authors.lastname: Giannoukos
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Bobrovnikova-Marjon
authors.forename: J Alan
authors.initials: JA
authors.lastname: Diehl
authors.forename: Brian
authors.initials: B
authors.lastname: Keith
authors.forename: M Celeste
authors.initials: MC
authors.lastname: Simon
mesh_terms: D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases / Q000172:deficiency / Q000235:genetics; D004734:Energy Metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology; D050356:Lipid Metabolism / Q000187:drug effects; D008055:Lipids / Q000096:biosynthesis / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology; D000076222:Mechanistic Target of Rapamycin Complex 1; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D046912:Multiprotein Complexes; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D010100:Oxygen / Q000378:metabolism / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D044967:Serum; D058570:TOR Serine-Threonine Kinases; D000077005:Tuberous Sclerosis Complex 2 Protein; D059016:Tumor Microenvironment; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics; D056811:Unfolded Protein Response
chemical_list: D000952:Antigens, Polyomavirus Transforming; D008055:Lipids; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D011506:Proteins; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C403982:ERN2 protein, human; C486556:Ern2 protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D004722:Endoribonucleases; D010100:Oxygen
keywords: ER stress; UPR; hypoxia; lipid desaturation; mTORC1; tumor microenvironment