Abstract
BackgroundGlutamine 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.MethodsThe 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.ResultsWe 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.ConclusionsThese 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.
Highlights
Glutamine metabolism is a central metabolic pathway in cancer
PGC-1α modulates the expression of enzymes involved in glutamine metabolism in ERBB2/Neu-induced breast cancer cells To assess the impact of PGC-1α on the expression of glutamine metabolism genes, we used clones of ERBB2/ Neu-induced breast cancer cells with modestly increased expression of PGC-1α (α-1.1 and α-1.2) and control cells (Ctl-1) [13]
Given the known functional relationship between PGC1α and the estrogen-related receptor α (ERRα) in the control of metabolism genes [10], we tested whether PGC-1α could be recruited at promoter sites targeted by ERRα using chromatin immunoprecipitation (ChIP) experiments
Summary
Reductive carboxylation of glutamine for lipogenesis has been shown to constitute a key anabolic route in cancer cells. Little is known regarding central regulators of the various glutamine metabolic pathways in cancer cells. Glutamine metabolism has been increasingly recognized as a central metabolic pathway in cancer, and it is thought that the catabolic and anabolic roles of glucose and glutamine cooperate in fuelling tumor growth [2]. Recent studies revealed that reductive carboxylation of glutamine to citrate through reversal of the citric acid cycle (CAC) and the subsequent use of citrate for lipogenesis constitute a key anabolic route in hypoxia in cancer cells, as well as in cancer cells with mitochondrial dysfunctions [5,6,7,8]. The ability to rely on this metabolic pathway will be a distinct advantage for solid tumors that experience fluctuating levels of oxygen by permitting elevated production of lipids, which are important notably for membrane biogenesis
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
