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.

Phospholipase D and the Maintenance of Phosphatidic Acid Levels for Regulation of Mammalian Target of Rapamycin (mTOR)

“…Albumin is a carrier protein for lipids (52), and thus, the scavenging of albumin also involves the scavenging of lipids. It was recently reported that constitutive mTORC1 activity renders hypoxic cells dependent on exogenous desaturated lipids for survival (53). Although this study did not connect the need for desaturated lipids and the dependence of mTOR on PA, it did provide further evidence for a lipid dependence of mTOR and potentially a dependence on desaturated lipids.…”

IRE1α RNase–dependent lipid homeostasis promotes survival in Myc-transformed cancers

“…35); and (c) previous work demonstrated that synthesizing or scavenging unsaturated lipids is critical to maintaining cell viability in multiple transformed cell types, especially encountering elevated protein synthesis (36,37). Decreased SCD1 protein accumulation upon IRE1α RNase inhibition was confirmed in multiple cell lines ( Figure 5C and Supplemental Figure 5, D and E).…”

“…However, to maintain ER homeostasis in cells with oncogene-driven protein synthesis, ER lipid membrane biogenesis must also be regulated to accommodate elevated protein load. For example, our previous studies revealed an essential role for unsaturated lipids in maintaining ER homeostasis and viability in cells with constitutive mTORC1 activity (48). The relationship between the UPR and ER lipid homeostasis is underscored by data demonstrating mutant IRE1α and PERK proteins lacking the ability to sense unfolded proteins retain their responsiveness to increased lipid saturation (49) and showing that SCD1 inhibition initiates ER stress in multiple conditions (50,51).…”

mTORC1 signaling activates NRF1 to increase cellular proteasome levels

“…mTORC1 plays a central role in the control of cell growth, and evidence indicate that the activation of SREBPdependent lipid synthesis is one essential downstream factor in its promotion of growth. 9,10 Recent studies have further suggested that, in parallel to its induction of protein synthesis, mTORC1 must also activate SREBP and de novo lipid synthesis in order to prevent ER stress, 36,37 which results from the accumulation of misfolded proteins in the ER. The essential nature of SREBP in the context of mTORC1 activation underlies a need to balance an increase in protein load in the ER and elsewhere with the expansion of ER and other cellular membranes through de novo lipid synthesis.…”