PGC1α Promotes Tumor Growth by Inducing Gene Expression Programs Supporting Lipogenesis

Despite the role of aerobic glycolysis in cancer, recent studies highlight the importance of the mitochondria and biosynthetic pathways as well. PPAR gamma coactivator 1 alpha (PGC1 alpha) is a key transcriptional regulator of several metabolic pathways including oxidative metabolism and lipogenesis. Initial studies suggested that PGC1 alpha expression is reduced in tumors compared with adjacent normal tissue. Paradoxically, other studies show that PGC1 alpha is associated with cancer cell proliferation. Therefore, the role of PGC1 alpha in cancer and especially carcinogenesis is unclear. Using Pgc1 alpha(-/-) and Pgc1 alpha(+/+) mice, we show that loss of PGC1 alpha protects mice from azoxymethane-induced colon carcinogenesis. Similarly, diethylnitrosamine-induced liver carcinogenesis is reduced in Pgc1 alpha(-/-) mice as compared with Pgc1 alpha(+/+) mice. Xenograft studies using gain and loss of PGC1 alpha expression showed that PGC1 alpha also promotes tumor growth. Interestingly, while PGC1 alpha induced oxidative phosphorylation and tricarboxylic acid cycle gene expression, we also observed an increase in the expression of two genes required for de novo fatty acid synthesis, ACC and FASN. In addition, SLC25A1 and ACLY, which are required for the conversion of glucose into acetyl-CoA for fatty acid synthesis, were also increased by PGC1 alpha, thus linking the oxidative and lipogenic functions of PGC1 alpha. Indeed, using stable C-13 isotope tracer analysis, we show that PGC1 alpha increased de novo lipogenesis. Importantly, inhibition of fatty acid synthesis blunted these progrowth effects of PGC1 alpha. In conclusion, these studies show for the first time that loss of PGC1 alpha protects against carcinogenesis and that PGC1 alpha coordinately regulates mitochondrial and fatty acid metabolism to promote tumor growth. Cancer Res; 71(21); 6888-98. (C) 2011 AACR.