PGC-1α supports glutamine metabolism in breast cancer

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.

A Tale of Two Glutaminases: Homologous Enzymes with Distinct Roles in Tumorigenesis

“…The transcription factor c-Myc indirectly upregulates GLS in some contexts by repressing the expression of miRNA-23 [96,107], which is also repressed by NF-κB [108]. The transcription factor c-Jun can directly bind to the GLS gene promoter and enhance expression, and other recent reports have shown that the transcriptional coactivator PGC-1α, and loss of the tumor suppressor Rb, increase GLS transcription and translation, respectively [109][110][111]. Of further note are recently suggested roles for members of the Sirtuin family of proteins in the regulation of GLS.…”

The Role of PGC1α in Cancer Metabolism and its Therapeutic Implications

“…Ectopic expression of PGC1a has been observed in several cancer types (50)(51)(52)(53), and it is regulated by several oncogenes and signaling pathways ( Fig. 1; refs.…”

“…The interaction of PGC1a and ERRa is required to promote OxPhos and glycolysis in an H-Ras V12 /KSR1-dependent manner to support anchorage-independent growth. Besides glucose use, glutamine utilization is also a characteristic feature of cancer metabolism (71), and the PGC1a/ERRa axis was reported to regulate glutaminolysis in the ErbB2/Neu-induced breast cancer model (51). This axis increases the expression of glutamine metabolism genes and manipulates glutamine-derived carbon flux into lipogenesis, which favors the proliferation of breast cancer cells in hypoxia.…”

Cancer metabolism in space and time: Beyond the Warburg effect

“…It has re cently been shown as a pos i tive or neg a tive metas ta sis reg u la tor in dif fer ent tu mor mod els. For in stance, PGC 1α/es tro gen re lated re cep tor α (ERRα) axis is crit i cal for breast can cer cells by in creas ing glu t a mine de rived car bon flux into li po ge n e sis no tably un der hy poxia, thereby sus tain ing their pro lif er a tion [183], but also by pro mot ing VEGF se cre tion and an gio gen e sis [184][185][186], thereby paving a plau si ble road for can cer cell dis sem i na tion. Breast cir cu lat ing can cer cells and par tic u larly those with a brain tro pism rely on PGC 1α en hanced mi to chon dr ial ac tiv ity dur ing metasta tic spread [132,187].…”