Dysregulated mTORC1 renders cells critically dependent on desaturated lipids for survival under tumor-like stress
- Regina M. Young1,2,
- Daniel Ackerman1,
- Zachary L. Quinn1,3,
- Anthony Mancuso4,
- Michaela Gruber1,5,
- Liping Liu1,3,6,
- Dionysios N. Giannoukos1,3,
- Ekaterina Bobrovnikova-Marjon1,7,
- J. Alan Diehl1,2,
- Brian Keith1,2 and
- M. Celeste Simon1,3,8
- 1Abramson Family Cancer Research Institute,
- 2Department of Cancer Biology,
- 3Howard Hughes Medical Institute,
- 4Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
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.
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Footnotes
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↵8 Corresponding author
E-mail celeste2{at}mail.med.upenn.edu
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.198630.112.
- Received June 15, 2012.
- Accepted April 23, 2013.
- Copyright © 2013 by Cold Spring Harbor Laboratory Press