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.
Keywords:
ER stress; UPR; hypoxia; lipid desaturation; mTORC1; tumor microenvironment.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, Polyomavirus Transforming / metabolism
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Autophagy / drug effects
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Cell Death / drug effects
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Cell Hypoxia*
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Cell Line, Tumor
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Cell Survival / drug effects
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Cell Transformation, Neoplastic
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Endoplasmic Reticulum Stress
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Endoribonucleases / deficiency
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Endoribonucleases / genetics
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Energy Metabolism
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Fibroblasts / drug effects
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Fibroblasts / metabolism*
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Fibroblasts / pathology
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Humans
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Kidney Neoplasms / metabolism
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Kidney Neoplasms / pathology
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Lipid Metabolism* / drug effects
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Lipids / biosynthesis
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Lipids / blood
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Lipids / chemistry*
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Lipids / pharmacology
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Mechanistic Target of Rapamycin Complex 1
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Membrane Proteins / deficiency
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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Multiprotein Complexes
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Neoplasms / metabolism*
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Neoplasms / pathology
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Oxygen / metabolism
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Oxygen / pharmacology
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Protein Serine-Threonine Kinases / deficiency
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Proteins / metabolism*
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Serum
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TOR Serine-Threonine Kinases
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Tuberous Sclerosis Complex 2 Protein
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Tumor Microenvironment
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Tumor Suppressor Protein p53 / deficiency
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Proteins / deficiency
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Tumor Suppressor Proteins / genetics
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Unfolded Protein Response
Substances
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Antigens, Polyomavirus Transforming
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Lipids
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Membrane Proteins
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Multiprotein Complexes
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Proteins
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TSC2 protein, human
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Tsc2 protein, mouse
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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ERN2 protein, human
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Ern2 protein, mouse
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Mechanistic Target of Rapamycin Complex 1
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Protein Serine-Threonine Kinases
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TOR Serine-Threonine Kinases
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Endoribonucleases
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Oxygen