Inhibition of mTOR complex 2 induces GSK3/FBXW7-dependent degradation of sterol regulatory element-binding protein 1 (SREBP1) and suppresses lipogenesis in cancer cells

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, a...

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Bibliographic Details
Published in:Oncogene 2016-02, Vol.35 (5), p.642-650
Main Authors: Li, S, Oh, Y-T, Yue, P, Khuri, F R, Sun, S-Y
Format: Article
Language:English
Subjects:
Acetyl-CoA carboxylase
Binding proteins
Cancer
Carcinogenesis
Cdc4 protein
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
Cell Line, Tumor
Cellular biology
Cellular signal transduction
Enzyme Inhibitors - pharmacology
F-Box Proteins - genetics
F-Box Proteins - metabolism
F-Box-WD Repeat-Containing Protein 7
Fatty-acid synthase
Gene Knockdown Techniques
Genetic aspects
Glycogen Synthase Kinase 3 - metabolism
HCT116 Cells
Health aspects
Humans
Indoles - pharmacology
Kinases
Lipogenesis
Maleimides - pharmacology
Mechanistic Target of Rapamycin Complex 2
Multiprotein Complexes - antagonists & inhibitors
Multiprotein Complexes - metabolism
Neoplasms - drug therapy
Neoplasms - metabolism
Neoplasms - pathology
Proteasomes
Protein expression
Rapamycin
Regulation
Signal transduction
Sterol Regulatory Element Binding Protein 1 - metabolism
Sterol regulatory element-binding protein
Sterols
TOR protein
TOR Serine-Threonine Kinases - antagonists & inhibitors
TOR Serine-Threonine Kinases - metabolism
Transcription
Transcription factors
Transfection
Tumor cell lines
Ubiquitin
Ubiquitin-protein ligase
Ubiquitin-Protein Ligases - genetics
Ubiquitin-Protein Ligases - metabolism
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Summary: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.
ISSN:0950-9232
1476-5594
DOI:10.1038/onc.2015.123