PGC-1α supports glutamine metabolism in breast cancer

Shawn McGuirk; Simon-Pierre Gravel; Geneviève Deblois; David J Papadopoli; Brandon Faubert; André Wegner; Karsten Hiller; Daina Avizonis; Uri David Akavia; Russell G Jones; Vincent Giguère; Julie St-Pierre

doi:10.1186/2049-3002-1-22

PGC-1α supports glutamine metabolism in breast cancer

Cancer Metab. 2013 Dec 5;1(1):22. doi: 10.1186/2049-3002-1-22.

Authors

Shawn McGuirk^#^{1

2}, Simon-Pierre Gravel^#^{1

2}, Geneviève Deblois^{1

2}, David J Papadopoli^{1

2}, Brandon Faubert^{1

3}, André Wegner⁴, Karsten Hiller⁴, Daina Avizonis^{1

5}, Uri David Akavia^{2

6

7}, Russell G Jones^{1

3}, Vincent Giguère^{1

2}, Julie St-Pierre^{1

2}

Affiliations

¹ Goodman Cancer Research Centre, McGill University, 1160 Pine Ave. West, Montréal, PQ H3A 1A3, Canada.
² Department of Biochemistry, McGill University, 3655 Promenade Sir-William-Osler, Montréal, PQ H3G 1Y6, Canada.
³ Department of Physiology, McGill University, 3655 Promenade Sir-William-Osler, Montréal, PQ H3G 1Y6, Canada.
⁴ Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7 Avenue des Hauts-Fourneaux, Esch-Belval L-4362, Luxembourg.
⁵ Metabolomics Core Facility, McGill University, 1160 Pine Ave. West, Montréal, PQ H3A 1A3, Canada.
⁶ Department of Biological Sciences, Columbia University, 1212 Amsterdam Ave, New York, NY 10027, USA.
⁷ Center for Computational Biology and Bioinformatics, Columbia University Medical Center, 1130 St. Nicholas Ave, New York, NY 10032, USA.

^# Contributed equally.

Abstract

Background: Glutamine metabolism is a central metabolic pathway in cancer. Recently, reductive carboxylation of glutamine for lipogenesis has been shown to constitute a key anabolic route in cancer cells. However, little is known regarding central regulators of the various glutamine metabolic pathways in cancer cells.

Methods: The impact of PGC-1α and ERRα on glutamine enzyme expression was assessed in ERBB2+ breast cancer cell lines with quantitative RT-PCR, chromatin immunoprecipitation, and immunoblotting experiments. Glutamine flux was quantified using 13C-labeled glutamine and GC/MS analyses. Functional assays for lipogenesis were performed using 14C-labeled glutamine. The expression of glutamine metabolism genes in breast cancer patients was determined by bioinformatics analyses using The Cancer Genome Atlas.

Results: We show that the transcriptional coactivator PGC-1α, along with the transcription factor ERRα, is a positive regulator of the expression of glutamine metabolism genes in ERBB2+ breast cancer. Indeed, ERBB2+ breast cancer cells with increased expression of PGC-1α display elevated expression of glutamine metabolism genes. Furthermore, ERBB2+ breast cancer cells with reduced expression of PGC-1α or when treated with C29, a pharmacological inhibitor of ERRα, exhibit diminished expression of glutamine metabolism genes. The biological relevance of the control of glutamine metabolism genes by the PGC-1α/ERRα axis is demonstrated by consequent regulation of glutamine flux through the citric acid cycle. PGC-1α and ERRα regulate both the canonical citric acid cycle (forward) and the reductive carboxylation (reverse) fluxes; the latter can be used to support de novo lipogenesis reactions, most notably in hypoxic conditions. Importantly, murine and human ERBB2+ cells lines display a significant dependence on glutamine availability for their growth. Finally, we show that PGC-1α expression is positively correlated with that of the glutamine pathway in ERBB2+ breast cancer patients, and high expression of this pathway is associated with reduced patient survival.

Conclusions: These data reveal that the PGC-1α/ERRα axis is a central regulator of glutamine metabolism in ERBB2+ breast cancer. This novel regulatory link, as well as the marked reduction in patient survival time associated with increased glutamine pathway gene expression, suggests that targeting glutamine metabolism may have therapeutic potential in the treatment of ERBB2+ breast cancer.