AMPK Promotes Aberrant PGC1β Expression To Support Human Colon Tumor Cell Survival.
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.
Eppley Institute, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Kurt W
KW
Fisher
Eppley Institute, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Binita
B
Das
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Hyun Seok
HS
Kim
Eppley Institute, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Beth K
BK
Clymer
Eppley Institute, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Drew
D
Gehring
Eppley Institute, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Deandra R
DR
Smith
Eppley Institute, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Diane L
DL
Costanzo-Garvey
Eppley Institute, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Mario R
MR
Fernandez
Eppley Institute, University of Nebraska Medical Center, Omaha, Nebraska, USA Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Michael G
MG
Brattain
Eppley Institute, University of Nebraska Medical Center, Omaha, Nebraska, USA.
David L
DL
Kelly
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas Texas, USA.
John
J
MacMillan
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA Michael.White@utsouthwestern.edu rlewis@unmc.edu.
Michael A
MA
White
Eppley Institute, University of Nebraska Medical Center, Omaha, Nebraska, USA Michael.White@utsouthwestern.edu rlewis@unmc.edu.
Robert E
RE
Lewis
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D003106:Colon / Q000378:metabolism / Q000473:pathology*; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism; D016601:RNA-Binding Proteins; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D000097983:ERRalpha Estrogen-Related Receptor
D055372:AMP-Activated Protein Kinases; D002352:Carrier Proteins; D011494:Protein Kinases; D021122:Protein Subunits; D016601:RNA-Binding Proteins; D011960:Receptors, Estrogen; D000097983:ERRalpha Estrogen-Related Receptor; C455622:PPARGC1B protein, human; C097199:KSR-1 protein kinase; C526181:PRKAA2 protein, human; C526183:PRKAB2 protein, human; C526222:PRKAG1 protein, human