Dysregulated mTORC1 renders cells critically dependent on desaturated lipids for survival under tumor-like stress
| Autor: | Ekaterina Bobrovnikova-Marjon, J. Alan Diehl, M. Celeste Simon, Daniel Ackerman, Zachary L. Quinn, Anthony A. Mancuso, Dionysios N. Giannoukos, Liping Liu, Michaela Gruber, Brian Keith, Regina M. Young |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Serum
Programmed cell death Cell Survival Antigens Polyomavirus Transforming mTORC1 Biology Mechanistic Target of Rapamycin Complex 1 Protein Serine-Threonine Kinases Mice Cell Line Tumor Neoplasms Endoribonucleases Tuberous Sclerosis Complex 2 Protein Genetics Autophagy Tumor Microenvironment Animals Humans Tumor microenvironment Cell Death Endoplasmic reticulum TOR Serine-Threonine Kinases Tumor Suppressor Proteins Membrane Proteins Proteins Metabolism Fibroblasts Endoplasmic Reticulum Stress Lipid Metabolism Lipids Cell Hypoxia Kidney Neoplasms Cell biology Oxygen Cell Transformation Neoplastic Cell culture Multiprotein Complexes Unfolded protein response Unfolded Protein Response TSC2 biological phenomena cell phenomena and immunity Tumor Suppressor Protein p53 Energy Metabolism Developmental Biology Research Paper |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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