AMPK Promotes Aberrant PGC1β Expression To Support Human Colon Tumor Cell Survival

Mol Cell Biol. 2015 Nov;35(22):3866-79. doi: 10.1128/MCB.00528-15. Epub 2015 Sep 8.

Abstract

A major goal of cancer research is the identification of tumor-specific vulnerabilities that can be exploited for the development of therapies that are selectively toxic to the tumor. We show here that the transcriptional coactivators peroxisome proliferator-activated receptor gamma coactivator 1β (PGC1β) and estrogen-related receptor α (ERRα) are aberrantly expressed in human colon cell lines and tumors. With kinase suppressor of Ras 1 (KSR1) depletion as a reference standard, we used functional signature ontology (FUSION) analysis to identify the γ1 subunit of AMP-activated protein kinase (AMPK) as an essential contributor to PGC1β expression and colon tumor cell survival. Subsequent analysis revealed that a subunit composition of AMPK (α2β2γ1) is preferred for colorectal cancer cell survival, at least in part, by stabilizing the tumor-specific expression of PGC1β. In contrast, PGC1β and ERRα are not detectable in nontransformed human colon epithelial cells, and depletion of the AMPKγ1 subunit has no effect on their viability. These data indicate that Ras oncogenesis relies on the aberrant activation of a PGC1β-dependent transcriptional pathway via a specific AMPK isoform.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Cell Line, Tumor
  • Cell Survival
  • Colon / metabolism
  • Colon / pathology*
  • Colonic Neoplasms / genetics*
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology
  • ERRalpha Estrogen-Related Receptor
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Mice, Inbred BALB C
  • Mice, Nude
  • Protein Kinases / genetics
  • Protein Kinases / metabolism
  • Protein Subunits / metabolism
  • RNA-Binding Proteins
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism

Substances

  • Carrier Proteins
  • PPARGC1B protein, human
  • Protein Subunits
  • RNA-Binding Proteins
  • Receptors, Estrogen
  • Protein Kinases
  • KSR-1 protein kinase
  • PRKAA2 protein, human
  • PRKAB2 protein, human
  • PRKAG1 protein, human
  • AMP-Activated Protein Kinases