Hyperglycemia-induced metabolic compensation inhibits metformin sensitivity in ovarian cancer

Lacey M. Litchfield, Abir Mukherjee, Mark A. Eckert, Alyssa Johnson, Kathryn A. Mills, Shawn Pan, Viji Shridhar, Ernst Lengyel, Iris L. Romero

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Increasing interest in repurposing the diabetic medication metformin for cancer treatment has raised important questions about the translation of promising preclinical findings to therapeutic efficacy, especially in non-diabetic patients. A significant limitation of the findings to date is the use of supraphysiologic metformin doses and hyperglycemic conditions in vitro. Our goals were to determine the impact of hyperglycemia on metformin response and to address the applicability of metformin as a cancer therapeutic in non-diabetic patients. In normoglycemic conditions, lower concentrations of metformin were required to inhibit cell viability, while metformin treatment in hyperglycemic conditions resulted in increased glucose uptake and glycolytic flux, contributing to cell survival. Mechanistically, maintenance of c-Myc expression under conditions of hyperglycemia or via gene amplification facilitated metabolic escape from the effects of metformin. In vivo, treatment of an ovarian cancer mouse model with metformin resulted in greater tumor weight reduction in normoglycemic vs. hyperglycemic mice, with increased c-Myc expression observed in metformin-treated hyperglycemic mice. These findings indicate that hyperglycemia inhibits the anti-cancer effects of metformin in vitro and in vivo. Furthermore, our results suggest that metformin may elicit stronger responses in normoglycemic vs. hyperglycemic patients, highlighting the need for prospective clinical testing in patients without diabetes.

Original languageEnglish (US)
Pages (from-to)23548-23560
Number of pages13
JournalOncotarget
Volume6
Issue number27
DOIs
StatePublished - 2015

Keywords

  • C-Myc
  • Glycolysis
  • Hyperglycemia
  • Metformin
  • Ovarian cancer

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Litchfield, L. M., Mukherjee, A., Eckert, M. A., Johnson, A., Mills, K. A., Pan, S., Shridhar, V., Lengyel, E., & Romero, I. L. (2015). Hyperglycemia-induced metabolic compensation inhibits metformin sensitivity in ovarian cancer. Oncotarget, 6(27), 23548-23560. https://doi.org/10.18632/oncotarget.4556