| First Author | Bhalla K | Year | 2011 |
| Journal | Cancer Res | Volume | 71 |
| Issue | 21 | Pages | 6888-98 |
| PubMed ID | 21914785 | Mgi Jnum | J:177378 |
| Mgi Id | MGI:5294874 | Doi | 10.1158/0008-5472.CAN-11-1011 |
| Citation | Bhalla K, et al. (2011) PGC1alpha Promotes Tumor Growth by Inducing Gene Expression Programs Supporting Lipogenesis. Cancer Res 71(21):6888-98 |
| abstractText | Despite the role of aerobic glycolysis in cancer, recent studies highlight the importance of the mitochondria and biosynthetic pathways as well. PPARgamma coactivator 1alpha (PGC1alpha) is a key transcriptional regulator of several metabolic pathways including oxidative metabolism and lipogenesis. Initial studies suggested that PGC1alpha expression is reduced in tumors compared with adjacent normal tissue. Paradoxically, other studies show that PGC1alpha is associated with cancer cell proliferation. Therefore, the role of PGC1alpha in cancer and especially carcinogenesis is unclear. Using Pgc1alpha(-/-) and Pgc1alpha(+/+) mice, we show that loss of PGC1alpha protects mice from azoxymethane-induced colon carcinogenesis. Similarly, diethylnitrosamine-induced liver carcinogenesis is reduced in Pgc1alpha(-/-) mice as compared with Pgc1alpha(+/+) mice. Xenograft studies using gain and loss of PGC1alpha expression showed that PGC1alpha also promotes tumor growth. Interestingly, while PGC1alpha 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 PGC1alpha, thus linking the oxidative and lipogenic functions of PGC1alpha. Indeed, using stable (13)C isotope tracer analysis, we show that PGC1alpha increased de novo lipogenesis. Importantly, inhibition of fatty acid synthesis blunted these progrowth effects of PGC1alpha. In conclusion, these studies show for the first time that loss of PGC1alpha protects against carcinogenesis and that PGC1alpha coordinately regulates mitochondrial and fatty acid metabolism to promote tumor growth. Cancer Res; 71(21); 6888-98. (c)2011 AACR. |
