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Loss of TSC2 confers resistance to ceramide and nutrient deprivation
G G Guenther1, G Liu1, M U Ramirez1
1Department of Developmental and Cell Biology, University of California, Irvine, CA, USA.
Abstract:
Nutrient stress that produces quiescence and catabolism in normal cells is lethal to cancer cells, because oncogenic mutations constitutively drive anabolism. One driver of biosynthesis in cancer cells is the mammalian target of rapamycin complex 1 (mTORC1) signaling complex. Activating mTORC1 by deleting its negative regulator tuberous sclerosis complex 2 (TSC2) leads to hypersensitivity to glucose deprivation. We have previously shown that ceramide kills cells in part by triggering nutrient transporter loss and restricting access to extracellular amino acids and glucose, suggesting that TSC2-deficient cells would be hypersensitive to ceramide. However, murine embryonic fibroblasts (MEFs) lacking TSC2 were highly resistant to ceramide-induced death. Consistent with the observation that ceramide limits access to both amino acids and glucose, TSC2(-/-) MEFs also had a survival advantage when extracellular amino acids and glucose were both reduced. As TSC2(-/-) MEFs were resistant to nutrient stress despite sustained mTORC1 activity, we assessed whether mTORC1 signaling might be beneficial under these conditions. In low amino acid and glucose medium, and following ceramide-induced nutrient transporter loss, elevated mTORC1 activity significantly enhanced the adaptive upregulation of new transporter proteins for amino acids and glucose. Strikingly, the introduction of oncogenic Ras abrogated the survival advantage of TSC2(-/-) MEFs upon ceramide treatment most likely by increasing nutrient demand. These results suggest that, in the absence of oncogene-driven biosynthetic demand, mTORC1-dependent translation facilitates the adaptive cellular response to nutrient stress.
Insights
Cancer cells, unlike normal cells, are vulnerable to nutrient stress. This study reveals that mTORC1 signaling aids cancer cells in adapting to nutrient deprivation by upregulating nutrient transporters, but oncogenic Ras overrides this survival mechanism.
Area of Science:
- Cellular metabolism
- Cancer biology
- Signal transduction
Background:
- Cancer cells exhibit constitutive anabolism, making them susceptible to nutrient stress.
- Mammalian target of rapamycin complex 1 (mTORC1) signaling drives biosynthesis in cancer.
- Tuberous sclerosis complex 2 (TSC2) loss activates mTORC1, causing glucose deprivation sensitivity.
Purpose of the Study:
- To investigate the role of mTORC1 signaling in cancer cell adaptation to nutrient stress, particularly ceramide-induced nutrient transporter loss.
- To determine if TSC2-deficient cells, with constitutive mTORC1 activity, are sensitive or resistant to ceramide.
- To explore the impact of oncogenic Ras on cancer cell survival under nutrient stress.
Main Methods:
- Utilized murine embryonic fibroblasts (MEFs) lacking TSC2 (TSC2(-/-)) to study mTORC1 activity.
- Applied ceramide treatment to induce nutrient transporter loss and nutrient deprivation (low amino acid and glucose).
- Introduced oncogenic Ras into TSC2(-/-) MEFs to assess its effect on survival.
Main Results:
- Contrary to expectations, TSC2(-/-) MEFs were resistant to ceramide-induced death and showed a survival advantage under combined amino acid and glucose reduction.
- Elevated mTORC1 activity in TSC2(-/-) MEFs enhanced adaptive upregulation of amino acid and glucose transporters during nutrient stress.
- Oncogenic Ras abrogated the survival advantage of TSC2(-/-) MEFs upon ceramide treatment, likely due to increased nutrient demand.
Conclusions:
- mTORC1 signaling promotes adaptive responses to nutrient stress by facilitating transporter upregulation when oncogene-driven demand is absent.
- Cancer cells' survival under nutrient stress is complex, influenced by both mTORC1 activity and oncogenic mutations.
- Targeting nutrient transporters and understanding the interplay between mTORC1 and oncogenes are crucial for cancer therapy.
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