title: PGC-1α promotes the growth of ErbB2/Neu-induced mammary tumors by regulating nutrient supply.
abstract: Cancer cells display an increased reliance on glycolysis despite the presence of sufficient oxygen levels to support mitochondrial functions. In this study, we asked whether ameliorating mitochondrial functions in cancer cells might limit their proliferative capacity. Specifically, we increased mitochondrial metabolism in a murine cellular model of ErbB2/Neu-induced breast cancer by ectopically expressing the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a master regulator of mitochondrial metabolism. As predicted, ErbB2/Neu cells ectopically expressing PGC-1α displayed an increased level of mitochondrial metabolism and reduced proliferative capacity in vitro, compared with controls. In contrast, ErbB2/Neu cells ectopically expressing PGC-1α formed larger tumors in vivo. These tumors exhibited increased concentrations of glucose and the angiogenic factor VEGF as well as higher expression of ErbB2/Neu compared with controls. We discovered that ErbB2/Neu levels were sensitive to nutrient availability, such that reduced glucose concentrations resulted in diminished ErbB2/Neu protein levels. Therefore, our data indicate that PGC-1α prevents the nutrient-mediated downregulation of ErbB2/Neu in tumors by increasing glucose supply. Mechanistic investigations revealed that the regulation of ErbB2/Neu levels by glucose was mediated by the unfolded protein response (UPR). Incubation of ErbB2/Neu-induced breast cancer cells in limited glucose concentrations or with drugs that activate the UPR led to significant reductions in ErbB2/Neu protein levels. Also, ErbB2/Neu-induced tumors ectopically expressing PGC-1α displayed lowered UPR activation compared with controls. Together, our findings uncover an unexpected link between PGC-1α-mediated nutrient availability, UPR, and ErbB2/Neu levels.
authors.affiliation: Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
authors.forename: Eva
authors.initials: E
authors.lastname: Klimcakova
authors.forename: Valérie
authors.initials: V
authors.lastname: Chénard
authors.forename: Shawn
authors.initials: S
authors.lastname: McGuirk
authors.forename: David
authors.initials: D
authors.lastname: Germain
authors.forename: Daina
authors.initials: D
authors.lastname: Avizonis
authors.forename: William J
authors.initials: WJ
authors.lastname: Muller
authors.forename: Julie
authors.initials: J
authors.lastname: St-Pierre
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005260:Female; D005947:Glucose / Q000032:analysis / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism*; D051379:Mice; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D056811:Unfolded Protein Response
chemical_list: D005947:Glucose; D006360:Heat-Shock Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D018719:Erb-b2 Receptor Tyrosine Kinases; D015534:Trans-Activators; D014157:Transcription Factors; C486497:PPARGC1A protein, human; C485290:Ppargc1a protein, mouse; C508053:ERBB2 protein, human; C524056:Erbb2 protein, mouse