title: Loss of TSC2 confers resistance to ceramide and nutrient deprivation.
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.
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, CA, USA.
authors.forename: G G
authors.initials: GG
authors.lastname: Guenther
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, CA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, CA, USA.
authors.forename: M U
authors.initials: MU
authors.lastname: Ramirez
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, CA, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: McMonigle
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, CA, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Kim
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, CA, USA.
authors.forename: A N
authors.initials: AN
authors.lastname: McCracken
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Joo
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, CA, USA.
authors.forename: I
authors.initials: I
authors.lastname: Ushach
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, CA, USA.
authors.forename: N L
authors.initials: NL
authors.lastname: Nguyen
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, CA, USA.
authors.forename: A L
authors.initials: AL
authors.lastname: Edinger
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D001692:Biological Transport; D002518:Ceramides / Q000494:pharmacology*; D003470:Culture Media / Q000737:chemistry; D005347:Fibroblasts / Q000378:metabolism*; D017353:Gene Deletion; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D015398:Signal Transduction; D013312:Stress, Physiological; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: D002518:Ceramides; D003470:Culture Media; D051272:Glucose Transporter Type 1; D046912:Multiprotein Complexes; C495678:Slc2a1 protein, mouse; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000255:Adenosine Triphosphate; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins; D005947:Glucose