PGC-1β and ERRα Promote Glutamine Metabolism and Colorectal Cancer Survival via Transcriptional Upregulation of PCK2

Previous studies have shown that Peroxisome Proliferator-Activated Receptor Gamma, Coactivator 1 Beta (PGC-1β) and Estrogen-Related Receptor Alpha (ERRα) are over-expressed in colorectal cancer and promote tumor survival. In this study, we use immunoprecipitation of epitope tagged endogenous PGC-1β...

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Bibliographic Details
Published in:Cancers 2022-10, Vol.14 (19), p.4879
Main Authors: Frodyma, Danielle E, Troia, Thomas C, Rao, Chaitra, Svoboda, Robert A, Berg, Jordan A, Shinde, Dhananjay D, Thomas, Vinai C, Lewis, Robert E, Fisher, Kurt W
Format: Article
Language:English
Subjects:
Amino acids
Antibodies
Cancer
Care and treatment
Cell culture
Cell survival
Colorectal cancer
Colorectal carcinoma
Epitopes
Estrogen
Gene expression
Genomics
Glutamine
Glutamine metabolism
Health aspects
Immunoprecipitation
Metabolism
Mitochondria
Mutagenesis
Patient outcomes
Phosphatase
Phosphotransferases
Proteins
Receptors
Sodium
Transcription
Transcription factors
Tricarboxylic acid cycle
Tumors
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Summary:Previous studies have shown that Peroxisome Proliferator-Activated Receptor Gamma, Coactivator 1 Beta (PGC-1β) and Estrogen-Related Receptor Alpha (ERRα) are over-expressed in colorectal cancer and promote tumor survival. In this study, we use immunoprecipitation of epitope tagged endogenous PGC-1β and inducible PGC-1β mutants to show that amino acid motif LRELL on PGC-1β is responsible for the physical interaction with ERRα and promotes ERRα mRNA and protein expression. We use RNAsequencing to determine the genes regulated by both PGC-1β & ERRα and find that mitochondrial Phosphoenolpyruvate Carboxykinase 2 (PCK2) is the gene that decreased most significantly after depletion of both genes. Depletion of PCK2 in colorectal cancer cells was sufficient to reduce anchorage-independent growth and inhibit glutamine utilization by the TCA cycle. Lastly, shRNA-mediated depletion of ERRα decreased anchorage-independent growth and glutamine metabolism, which could not be rescued by plasmid derived expression of PCK2. These findings suggest that transcriptional control of PCK2 is one mechanism used by PGC-1β and ERRα to promote glutamine metabolism and colorectal cancer cell survival.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers14194879