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Glutamine activates STAT3 to control cancer cell proliferation independently of glutamine metabolism

Oncogene volume 36, pages 2074–2084 (2017)Cite this article

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Abstract

Cancer cells can use a variety of metabolic substrates to fulfill the bioenergetic and biosynthetic needs of their oncogenic program. Besides bioenergetics, cancer cell metabolism also directly influences genetic, epigenetic and signaling events associated with tumor progression. Many cancer cells are addicted to glutamine, and this addiction is observed in oxidative as well as in glycolytic cells. Although both oxidative and bioreductive glutamine metabolism can contribute to cancer progression and glutamine can further serve to generate peptides (including glutathione) and proteins, we report that glutamine promotes the proliferation of cancer cells independently of its use as a metabolic fuel or as a precursor of glutathione. Extracellular glutamine activates transcription factor signal transducer and activator of transcription 3 (STAT3), which is necessary and sufficient to mediate the proliferative effects of glutamine on glycolytic and oxidative cancer cells. Glutamine also activates transcription factors hypoxia-inducible factor-1, mammalian target of rapamycin and c-Myc, but these factors do not mediate the effects of glutamine on cancer cell proliferation. Our findings shed a new light on the anticancer effects of l-asparaginase that possesses glutaminase activity and converts glutamine into glutamate extracellularly. Conversely, cancer resistance to treatments that block glutamine metabolism could arise from glutamine-independent STAT3 reactivation.

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Acknowledgements

This work was supported by a Starting Grant from the European Research Council (ERC no. 243188 TUMETABO), Interuniversity Attraction Pole (IAP) grant #UP7-03 from the Belgian Science Policy Office (Belspo), an Action de Recherche Concertée from the Communauté Française de Belgique (ARC 14/19-058), the Belgian Fonds National de la Recherche Scientifique (FRS-FNRS), the Télévie and the Belgian Fondation contre le Cancer (2012-186). PS is a FRS-FNRS Research Associate. AC is a Postdoctoral Fellow and MS a Research Fellow of the Télévie. We thank Marylène Focant from Promega (Leiden, The Netherlands) for having provided glutamine/glutamate-Glo Assay kits.

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  1. A Cacace and M Sboarina: Co-first authors contributed equally to this work.

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  1. Pole of Pharmacology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), Brussels, Belgium

    A Cacace, M Sboarina, T Vazeille & P Sonveaux

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Cacace, A., Sboarina, M., Vazeille, T. et al. Glutamine activates STAT3 to control cancer cell proliferation independently of glutamine metabolism. Oncogene 36, 2074–2084 (2017). https://doi.org/10.1038/onc.2016.364

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