Abstract
Dysregulated mammalian target of rapamycin (mTOR) promotes cancer, but underlying mechanisms are poorly understood. We describe an mTOR-driven mouse model that displays hepatosteatosis progressing to hepatocellular carcinoma (HCC). Longitudinal proteomic, lipidomics, and metabolomic analyses revealed that hepatic mTORC2 promotes de novo fatty acid and lipid synthesis, leading to steatosis and tumor development. In particular, mTORC2 stimulated sphingolipid (glucosylceramide) and glycerophospholipid (cardiolipin) synthesis. Inhibition of fatty acid or sphingolipid synthesis prevented tumor development, indicating a causal effect in tumorigenesis. Increased levels of cardiolipin were associated with tubular mitochondria and enhanced oxidative phosphorylation. Furthermore, increased lipogenesis correlated with elevated mTORC2 activity and HCC in human patients. Thus, mTORC2 promotes cancer via formation of lipids essential for growth and energy production.
Highlights
Cancer is a disorder characterized by increased metabolic activity leading to enhanced cell growth and proliferation
In a mouse model that develops hepatosteatosis and liver cancer, we find that mTORC2 promotes fatty acid, sphingolipid, and glycerophospholipid synthesis, and thereby tumorigenesis
Liver-Specific Activation of mammalian target of rapamycin (mTOR) Signaling Promotes fatty acid (FA) Synthesis, Hepatosteatosis, and hepatocellular carcinoma (HCC) To study the role of mTOR signaling in cancer, we generated mice lacking Tsc1 and Pten in the liver
Summary
Cancer is a disorder characterized by increased metabolic activity leading to enhanced cell growth and proliferation. Cancer cells exhibit metabolic features that are distinct from non-cancerous cells (Hanahan and Weinberg, 2011; Pavlova and Thompson, 2016). One such feature is elevated fatty acid (FA) synthesis; non-cancerous cells rely on exogenous sources (Schulze and Harris, 2012). Various enzymes that mediate FA and lipid synthesis are transcriptionally upregulated in tumors (Menendez and Lupu, 2007). NAFLD is characterized in part by excessive accumulation of triglycerides (TGs) in hepatocytes ( known as hepatosteatosis), due to enhanced hepatic de novo FA synthesis (Lambert et al, 2014)
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
