title: PGC1α promotes tumor growth by inducing gene expression programs supporting lipogenesis.
abstract: Despite the role of aerobic glycolysis in cancer, recent studies highlight the importance of the mitochondria and biosynthetic pathways as well. PPARγ coactivator 1α (PGC1α) is a key transcriptional regulator of several metabolic pathways including oxidative metabolism and lipogenesis. Initial studies suggested that PGC1α expression is reduced in tumors compared with adjacent normal tissue. Paradoxically, other studies show that PGC1α is associated with cancer cell proliferation. Therefore, the role of PGC1α in cancer and especially carcinogenesis is unclear. Using Pgc1α(-/-) and Pgc1α(+/+) mice, we show that loss of PGC1α protects mice from azoxymethane-induced colon carcinogenesis. Similarly, diethylnitrosamine-induced liver carcinogenesis is reduced in Pgc1α(-/-) mice as compared with Pgc1α(+/+) mice. Xenograft studies using gain and loss of PGC1α expression showed that PGC1α also promotes tumor growth. Interestingly, while PGC1α 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 PGC1α, thus linking the oxidative and lipogenic functions of PGC1α. Indeed, using stable (13)C isotope tracer analysis, we show that PGC1α increased de novo lipogenesis. Importantly, inhibition of fatty acid synthesis blunted these progrowth effects of PGC1α. In conclusion, these studies show for the first time that loss of PGC1α protects against carcinogenesis and that PGC1α coordinately regulates mitochondrial and fatty acid metabolism to promote tumor growth.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, Maryland, USA.
authors.forename: Kavita
authors.initials: K
authors.lastname: Bhalla
authors.forename: Bor Jang
authors.initials: BJ
authors.lastname: Hwang
authors.forename: Ruby E
authors.initials: RE
authors.lastname: Dewi
authors.forename: Lihui
authors.initials: L
authors.lastname: Ou
authors.forename: William
authors.initials: W
authors.lastname: Twaddel
authors.forename: Hong-Bin
authors.initials: HB
authors.lastname: Fang
authors.forename: Scott B
authors.initials: SB
authors.lastname: Vafai
authors.forename: Francesca
authors.initials: F
authors.lastname: Vazquez
authors.forename: Pere
authors.initials: P
authors.lastname: Puigserver
authors.forename: Laszlo
authors.initials: L
authors.lastname: Boros
authors.forename: Geoffrey D
authors.initials: GD
authors.lastname: Girnun
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor / Q000378:metabolism / Q000637:transplantation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002952:Citric Acid Cycle / Q000235:genetics; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D064429:Fatty Acid Synthases / Q000096:biosynthesis / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D050155:Lipogenesis / Q000235:genetics*; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000517:prevention & control*; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins; D009368:Neoplasm Transplantation; D027361:Organic Anion Transporters / Q000096:biosynthesis / Q000235:genetics; D010085:Oxidative Phosphorylation; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors
chemical_list: D005227:Fatty Acids; D024101:Mitochondrial Proteins; D027361:Organic Anion Transporters; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C569035:Slc25a1 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D064429:Fatty Acid Synthases; D000103:Acetyl-CoA Carboxylase