AMPK Promotes Aberrant PGC1 beta Expression To Support Human Colon Tumor Cell Survival

作者：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 L; MacMillan John; White Michael A^*; Lewis Robert E

来源：Molecular and Cellular Biology, 2015, 35(22): 3866-3879.

DOI：10.1128/MCB.00528-15

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 1 beta (PGC1 beta) and estrogen-related receptor alpha (ERR alpha) 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 gamma 1 subunit of AMP-activated protein kinase (AMPK) as an essential contributor to PGC1 beta expression and colon tumor cell survival. Subsequent analysis revealed that a subunit composition of AMPK (alpha 2 beta 2 gamma 1) is preferred for colorectal cancer cell survival, at least in part, by stabilizing the tumor-specific expression of PGC1 beta. In contrast, PGC1 beta and ERR alpha are not detectable in nontransformed human colon epithelial cells, and depletion of the AMPK gamma 1 subunit has no effect on their viability. These data indicate that Ras oncogenesis relies on the aberrant activation of a PGC1 beta-dependent transcriptional pathway via a specific AMPK isoform.

• 出版日期2015-11