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

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.

View publisher note:

Article of Significant Interest Selected from This Issue by the Editors

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00528-15.

ACKNOWLEDGMENTS

We thank Amy Wells from the University of Nebraska Medical Center (UNMC) Eppley Institute high-throughput screening facility for her assistance in performing the genome-scale screen, the UNMC Cell Analysis Facility for performing the flow cytometry analysis, and the UNMC Tissue Sciences Facility for providing us with normal colon and colon tumor tissue microarrays. We acknowledge Premila Leiphrakpam for her support throughout this project. We thank Rob Livergood for his contribution in the quantification of the in situ hybridization.

This work was supported by grants from NCI (CA157774 to R.E.L.), NIH (CA071443 to M.A.W and CA1499833 to J.M.), and the Nebraska Department of Health and Human Services (LB506 to R.E.L.) and by an Eppley Institute Cancer Biology training grant (NCI T32CA009476) and Fred and Pamela Buffett Cancer Center support grant (P30CA036727).

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. We declare that we have no conflicts of interests.