AMPK promotes aberrant PGC1ß expression to support human colon tumor cell survival

Kurt W. Fisher, Binita Das, Hyun Seok Kim, Beth K. Clymer, Drew Gehring, Deandra R. Smith, Diane L. Costanzo-Garvey, Mario R. Fernandez, Michael G. Brattain, David Lee Kelly, John MacMillan, Michael A. White, Robert E Lewis

Research output: Contribution to journalArticle

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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 proliferatoractivated receptor gamma coactivator 1ß (PGC1ß) 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 PGC1ß expression and colon tumor cell survival. Subsequent analysis revealed that a subunit composition of AMPK (α2ß2γ1) is preferred for colorectal cancer cell survival, at least in part, by stabilizing the tumor-specific expression of PGC1ß. In contrast, PGC1ß 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 PGC1ß-dependent transcriptional pathway via a specific AMPK isoform.

Original languageEnglish (US)
Pages (from-to)3866-3879
Number of pages14
JournalMolecular and cellular biology
Volume35
Issue number22
DOIs
StatePublished - Jan 1 2015

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AMP-Activated Protein Kinases
Cell Survival
Colon
Neoplasms
Peroxisomes
Poisons
Tumor Cell Line
Colorectal Neoplasms
Protein Isoforms
Carcinogenesis
Epithelial Cells
Research

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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AMPK promotes aberrant PGC1ß expression to support human colon tumor cell survival. / Fisher, Kurt W.; Das, Binita; Kim, Hyun Seok; Clymer, Beth K.; Gehring, Drew; Smith, Deandra R.; Costanzo-Garvey, Diane L.; Fernandez, Mario R.; Brattain, Michael G.; Kelly, David Lee; MacMillan, John; White, Michael A.; Lewis, Robert E.

In: Molecular and cellular biology, Vol. 35, No. 22, 01.01.2015, p. 3866-3879.

Research output: Contribution to journalArticle

Fisher, KW, Das, B, Kim, HS, Clymer, BK, Gehring, D, Smith, DR, Costanzo-Garvey, DL, Fernandez, MR, Brattain, MG, Kelly, DL, MacMillan, J, White, MA & Lewis, RE 2015, 'AMPK promotes aberrant PGC1ß expression to support human colon tumor cell survival', Molecular and cellular biology, vol. 35, no. 22, pp. 3866-3879. https://doi.org/10.1128/MCB.00528-15
Fisher, Kurt W. ; Das, Binita ; Kim, Hyun Seok ; Clymer, Beth K. ; Gehring, Drew ; Smith, Deandra R. ; Costanzo-Garvey, Diane L. ; Fernandez, Mario R. ; Brattain, Michael G. ; Kelly, David Lee ; MacMillan, John ; White, Michael A. ; Lewis, Robert E. / AMPK promotes aberrant PGC1ß expression to support human colon tumor cell survival. In: Molecular and cellular biology. 2015 ; Vol. 35, No. 22. pp. 3866-3879.
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