The PGC-1α/ERRα Axis Represses One-Carbon Metabolism and Promotes Sensitivity to Anti-folate Therapy in Breast Cancer

Cell Rep. 2016 Feb 2;14(4):920-931. doi: 10.1016/j.celrep.2015.12.086. Epub 2016 Jan 21.

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.

Keywords: AMPK; folate; metabolic reprogramming; methotrexate; nuclear receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Animals
  • Antimetabolites, Antineoplastic / pharmacology*
  • Breast Neoplasms / metabolism*
  • Cell Line
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Female
  • Folic Acid / metabolism
  • Folic Acid Antagonists / pharmacology*
  • Humans
  • Methotrexate / pharmacology*
  • Mice
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Purines / biosynthesis
  • Receptors, Estrogen / metabolism*
  • Transcription Factors / metabolism*

Substances

  • Antimetabolites, Antineoplastic
  • ERRalpha estrogen-related receptor
  • Folic Acid Antagonists
  • PPARGC1A protein, human
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Purines
  • Receptors, Estrogen
  • Transcription Factors
  • Folic Acid
  • AMP-Activated Protein Kinases
  • purine
  • Methotrexate