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PGC1α promotes tumor growth by inducing gene expression programs supporting lipogenesis
Kavita Bhalla1, Bor Jang Hwang, Ruby E Dewi
1Department of Biochemistry and Molecular Biology, University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, Maryland, USA.
Cancer Research
|September 15, 2011
Summary
Loss of PPARγ coactivator 1α (PGC1α) protects against colon and liver cancer. PGC1α promotes tumor growth by coordinating mitochondrial and fatty acid metabolism.
Area of Science:
- Metabolic regulation in cancer
- Mitochondrial function and cancer
- Lipogenesis and carcinogenesis
Background:
- Aerobic glycolysis is crucial in cancer, but mitochondria and biosynthesis are also important.
- PPARγ coactivator 1α (PGC1α) regulates oxidative metabolism and lipogenesis.
- The role of PGC1α in cancer and carcinogenesis is unclear due to conflicting study findings.
Purpose of the Study:
- To investigate the role of PGC1α in cancer and carcinogenesis.
- To determine how PGC1α influences metabolic pathways in tumor growth.
Main Methods:
- Utilized Pgc1α(-/-) and Pgc1α(+/+) mice for carcinogenesis studies.
- Employed xenograft models with altered PGC1α expression.
- Conducted stable (13)C isotope tracer analysis to assess de novo lipogenesis.
- Investigated gene expression related to oxidative phosphorylation and fatty acid synthesis.
Main Results:
- Loss of PGC1α protected against azoxymethane-induced colon and diethylnitrosamine-induced liver carcinogenesis.
- PGC1α expression promoted tumor growth in xenograft models.
- PGC1α upregulated oxidative phosphorylation and tricarboxylic acid cycle genes.
- PGC1α increased de novo fatty acid synthesis genes (ACC, FASN) and glucose conversion enzymes (SLC25A1, ACLY).
- Stable isotope tracer analysis confirmed PGC1α-driven de novo lipogenesis.
- Inhibition of fatty acid synthesis abolished PGC1α's tumor-promoting effects.
Conclusions:
- Loss of PGC1α confers protection against carcinogenesis.
- PGC1α promotes tumor growth by coordinately regulating mitochondrial and fatty acid metabolism.
- Targeting fatty acid synthesis may be a strategy to counteract PGC1α-driven tumor progression.
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