title: The PGC-1α/ERRα Axis Represses One-Carbon Metabolism and Promotes Sensitivity to Anti-folate Therapy in Breast Cancer.
abstract: Reprogramming of cellular metabolism plays a central role in fueling malignant transformation, and AMPK and the PGC-1α/ERRα axis are key regulators of this process. The intersection of gene-expression and binding-event datasets for breast cancer cells shows that activation of AMPK significantly increases the expression of PGC-1α/ERRα and promotes the binding of ERRα to its cognate sites. Unexpectedly, the data also reveal that ERRα, in concert with PGC-1α, negatively regulates the expression of several one-carbon metabolism genes, resulting in substantial perturbations in purine biosynthesis. This PGC-1α/ERRα-mediated repression of one-carbon metabolism promotes the sensitivity of breast cancer cells and tumors to the anti-folate drug methotrexate. These data implicate the PGC-1α/ERRα axis as a core regulatory node of folate cycle metabolism and further suggest that activators of AMPK could be used to modulate this pathway in cancer.
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada.
authors.forename: Étienne
authors.initials: É
authors.lastname: Audet-Walsh
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, QC H3G 1Y6, Canada.
authors.forename: David J
authors.initials: DJ
authors.lastname: Papadopoli
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada.
authors.forename: Simon-Pierre
authors.initials: SP
authors.lastname: Gravel
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, QC H3G 1Y6, Canada.
authors.forename: Tracey
authors.initials: T
authors.lastname: Yee
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Bridon
authors.affiliation: McGill University and Génome Québec Innovation Centre, Montréal, QC H3A 0G1, Canada.
authors.forename: Maxime
authors.initials: M
authors.lastname: Caron
authors.affiliation: McGill University and Génome Québec Innovation Centre, Montréal, QC H3A 0G1, Canada; Department of Human Genetics, McGill University, Montréal, QC H3G 1Y6, Canada.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bourque
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, QC H3G 1Y6, Canada; Departments of Medicine and Oncology, McGill University, Montréal, QC H3G 1Y6, Canada. Electronic address: vincent.giguere@mcgill.ca.
authors.forename: Vincent
authors.initials: V
authors.lastname: Giguère
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, QC H3G 1Y6, Canada. Electronic address: julie.st-pierre@mcgill.ca.
authors.forename: Julie
authors.initials: J
authors.lastname: St-Pierre
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D005492:Folic Acid / Q000378:metabolism; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D006801:Humans; D008727:Methotrexate / Q000494:pharmacology*; D051379:Mice; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011687:Purines / Q000096:biosynthesis; D011960:Receptors, Estrogen / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D055372:AMP-Activated Protein Kinases; D000964:Antimetabolites, Antineoplastic; D005492:Folic Acid; D005493:Folic Acid Antagonists; D008727:Methotrexate; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011687:Purines; D011960:Receptors, Estrogen; D014157:Transcription Factors; D000097983:ERRalpha Estrogen-Related Receptor; C486497:PPARGC1A protein, human; C030985:purine
keywords: AMPK; folate; metabolic reprogramming; methotrexate; nuclear receptor