title: Hyperglycemia-induced metabolic compensation inhibits metformin sensitivity in ovarian cancer.
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.
authors.affiliation: Department of Obstetrics and Gynecology, Gordon Center for Integrative Science, University of Chicago, Chicago, Illinois, USA.
authors.forename: Lacey M
authors.initials: LM
authors.lastname: Litchfield
authors.affiliation: Department of Obstetrics and Gynecology, Gordon Center for Integrative Science, University of Chicago, Chicago, Illinois, USA.
authors.forename: Abir
authors.initials: A
authors.lastname: Mukherjee
authors.affiliation: Department of Obstetrics and Gynecology, Gordon Center for Integrative Science, University of Chicago, Chicago, Illinois, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Eckert
authors.affiliation: Department of Obstetrics and Gynecology, Gordon Center for Integrative Science, University of Chicago, Chicago, Illinois, USA.
authors.forename: Alyssa
authors.initials: A
authors.lastname: Johnson
authors.affiliation: Department of Obstetrics and Gynecology, Gordon Center for Integrative Science, University of Chicago, Chicago, Illinois, USA.
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Mills
authors.affiliation: Department of Obstetrics and Gynecology, Gordon Center for Integrative Science, University of Chicago, Chicago, Illinois, USA.
authors.forename: Shawn
authors.initials: S
authors.lastname: Pan
authors.affiliation: Department of Laboratory Medicine and Experimental Pathology, Mayo Clinic Cancer Center, Rochester, Minnesota, USA.
authors.forename: Viji
authors.initials: V
authors.lastname: Shridhar
authors.affiliation: Department of Obstetrics and Gynecology, Gordon Center for Integrative Science, University of Chicago, Chicago, Illinois, USA.
authors.forename: Ernst
authors.initials: E
authors.lastname: Lengyel
authors.affiliation: Department of Obstetrics and Gynecology, Gordon Center for Integrative Science, University of Chicago, Chicago, Illinois, USA.
authors.forename: Iris L
authors.initials: IL
authors.lastname: Romero
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D001201:Ascites / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000737:chemistry; D019344:Lactic Acid / Q000737:chemistry; D020935:MAP Kinase Signaling System; D008687:Metformin / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D010427:Pentose Phosphate Pathway; D010629:Phenformin / Q000737:chemistry; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D007004:Hypoglycemic Agents; D016271:Proto-Oncogene Proteins c-myc; D019344:Lactic Acid; D008687:Metformin; D010629:Phenformin; D005947:Glucose
keywords: c-Myc; glycolysis; hyperglycemia; metformin; ovarian cancer