Metabolic vulnerabilities in endometrial cancer

Frances L. Byrne, Ivan K.H. Poon, Susan C. Modesitt, Jose L. Tomsig, Jenny D.Y. Chow, Marin E. Healy, William D. Baker, Kristen A. Atkins, Johnathan M. Lancaster, Douglas C. Marchion, Kelle H. Moley, Kodi S. Ravichandran, Jill K. Slack-Davis, Kyle L. Hoehn

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

Women with metabolic disorders, including obesity and diabetes, have an increased risk of developing endometrial cancer. However, the metabolism of endometrial tumors themselves has been largely understudied. Comparing human endometrial tumors and cells with their nonmalignant counterparts, we found that upregulation of the glucose transporter GLUT6 was more closely associated with the cancer phenotype than other hallmark cancer genes, including hexokinase 2 and pyruvate kinase M2. Importantly, suppression of GLUT6 expression inhibited glycolysis and survival of endometrial cancer cells. Glycolysis and lipogenesis were also highly coupled with the cancer phenotype in patient samples and cells. To test whether targeting endometrial cancer metabolism could be exploited as a therapeutic strategy, we screened a panel of compounds known to target diverse metabolic pathways in endometrial cells. We identified that the glycolytic inhibitor, 3-bromopyruvate, is a powerful antagonist of lipogenesis through pyruvylation of CoA. We also provide evidence that 3-bromopyruvate promotes cell death via a necrotic mechanism that does not involve reactive oxygen species and that 3-bromopyruvate impaired the growth of endometrial cancer xenografts.

Original languageEnglish
Pages (from-to)5832-5845
Number of pages14
JournalCancer research
Volume74
Issue number20
DOIs
StatePublished - Oct 15 2014

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    Byrne, F. L., Poon, I. K. H., Modesitt, S. C., Tomsig, J. L., Chow, J. D. Y., Healy, M. E., Baker, W. D., Atkins, K. A., Lancaster, J. M., Marchion, D. C., Moley, K. H., Ravichandran, K. S., Slack-Davis, J. K., & Hoehn, K. L. (2014). Metabolic vulnerabilities in endometrial cancer. Cancer research, 74(20), 5832-5845. https://doi.org/10.1158/0008-5472.CAN-14-0254