title: Metformin Targets Central Carbon Metabolism and Reveals Mitochondrial Requirements in Human Cancers.
abstract: Repurposing metformin for cancer therapy is attractive due to its safety profile, epidemiological evidence, and encouraging data from human clinical trials. Although it is known to systemically affect glucose metabolism in liver, muscle, gut, and other tissues, the molecular determinants that predict a patient response in cancer remain unknown. Here, we carry out an integrative metabolomics analysis of metformin action in ovarian cancer. Metformin accumulated in patient biopsies, and pathways involving nucleotide metabolism, redox, and energy status, all related to mitochondrial metabolism, were affected in treated tumors. Strikingly, a metabolic signature obtained from a patient with an exceptional clinical outcome mirrored that of a responsive animal tumor. Mechanistically, we demonstrate with stable isotope tracing that these metabolic signatures are due to an inability to adapt nutrient utilization in the mitochondria. This analysis provides new insights into mitochondrial metabolism and may lead to more precise indications of metformin in cancer.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke Cancer Institute, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Liu
authors.affiliation: Section of Gynecologic Oncology, Department of Obstetrics and Gynecology, Center for Integrative Science, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Iris L
authors.initials: IL
authors.lastname: Romero
authors.affiliation: Section of Gynecologic Oncology, Department of Obstetrics and Gynecology, Center for Integrative Science, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Lacey M
authors.initials: LM
authors.lastname: Litchfield
authors.affiliation: Section of Gynecologic Oncology, Department of Obstetrics and Gynecology, Center for Integrative Science, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Ernst
authors.initials: E
authors.lastname: Lengyel
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke Cancer Institute, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: jason.locasale@duke.edu.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Locasale
mesh_terms: D000818:Animals; D002244:Carbon / Q000378:metabolism*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005260:Female; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D055442:Metabolome / Q000187:drug effects; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D013379:Substrate Specificity / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D002244:Carbon; D008687:Metformin; D005947:Glucose
keywords: cell proliferation; flux analysis; mass spectrometry; metabolomics; mitochondria; network analysis; ovarian cancer; systems biology