title: Inhibition of mTOR complex 2 induces GSK3/FBXW7-dependent degradation of sterol regulatory element-binding protein 1 (SREBP1) and suppresses lipogenesis in cancer cells.
abstract: Cancer cells feature increased de novo lipogenesis. Sterol regulatory element-binding protein 1 (SREBP1), when presented in its mature form (mSREBP1), enhances lipogenesis by increasing transcription of several of its target genes. Mammalian target of rapamycin (mTOR) complexes, mTORC1 and mTORC2, are master regulators of cellular survival, growth and metabolism. A role for mTORC1 in the regulation of SREBP1 activity has been suggested; however, the connection between mTORC2 and SREBP1 has not been clearly established and hence is the focus of this study. mTOR kinase inhibitors (for example, INK128), which inhibit both mTORC1 and mTORC2, decreased mSREBP1 levels in various cancer cell lines. Knockdown of rictor, but not raptor, also decreased mSREBP1. Consistently, reduced mSREBP1 levels were detected in cells deficient in rictor or Sin1 compared with parent or rictor-deficient cells with re-expression of ectopic rictor. Hence it is mTORC2 inhibition that causes mSREBP1 reduction. As a result, expression of the mSREBP1 target genes acetyl-CoA carboxylase and fatty-acid synthase was suppressed, along with suppressed lipogenesis in cells exposed to INK128. Moreover, mSREBP1 stability was reduced in cells treated with INK128 or rictor knockdown. Inhibition of proteasome, GSK3 or the E3 ubiquitin ligase, FBXW7, prevented mSREBP1 reduction induced by mTORC2 inhibition. Thus mTORC2 inhibition clearly facilitates GSK3-dependent, FBXW7-mediated mSREBP1 degradation, leading to mSREBP1 reduction. Accordingly, we conclude that mTORC2 positively regulates mSREBP1 stability and lipogenesis. Our findings reveal a novel biological function of mTORC2 in the regulation of lipogenesis and warrant further study in this direction.
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.|Department of Biochemistry and Molecular Biology, Beijing Institute of Basic Medical Sciences, Beijing, People's Republic of China.
authors.forename: S
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.
authors.forename: Y-T
authors.initials: YT
authors.lastname: Oh
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Yue
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.
authors.forename: F R
authors.initials: FR
authors.lastname: Khuri
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.
authors.forename: S-Y
authors.initials: SY
authors.lastname: Sun
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D055785:Gene Knockdown Techniques; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D045325:HCT116 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D050155:Lipogenesis; D008301:Maleimides / Q000494:pharmacology; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D007211:Indoles; D008301:Maleimides; D046912:Multiprotein Complexes; C417521:SB 216763; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D044767:Ubiquitin-Protein Ligases; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3