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Increased efficacy of metformin corresponds to differential metabolic effects in the ovarian tumors from obese versus lean mice

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dc.contributor.authorHan, Jianjunen
dc.contributor.authorWysham, Weiya Z.en
dc.contributor.authorZhong, Yanen
dc.contributor.authorGuo, Huien
dc.contributor.authorZhang, Luen
dc.contributor.authorMalloy, Kim M.en
dc.contributor.authorDickens, Hallum K.en
dc.contributor.authorHuh, Geneen
dc.contributor.authorLee, Douglasen
dc.contributor.authorMakowski, Lizaen
dc.contributor.authorZhou, Chunxiaoen
dc.contributor.authorBae-Jump, Victoria L.en
dc.date.accessioned2019-09-17T19:20:03Zen
dc.date.available2019-09-17T19:20:03Zen
dc.date.issued2017-12-19en
dc.description.abstractObesity is a significant risk factor for ovarian cancer (OC) and associated with worse outcomes for this disease. We assessed the anti-tumorigenic effects of metformin in human OC cell lines and a genetically engineered mouse model of high grade serous OC under obese and lean conditions. Metformin potently inhibited growth in a dose-dependent manner in all four human OC cell lines through AMPK/mTOR pathways. Treatment with metformin resulted in G1 arrest, induction of apoptosis, reduction of invasion and decreased hTERT expression. In the K18-gT(121)(+/-); p53(fl/fl); Brca1(fl/fl) (KpB) mouse model, metformin inhibited tumor growth in both lean and obese mice. However, in the obese mice, metformin decreased tumor growth by 60%, whereas tumor growth was only decreased by 32% in the lean mice (p=0.003) compared to vehicle-treated mice. The ovarian tumors from obese mice had evidence of impaired mitochondrial complex 2 function and energy supplied by omega fatty acid oxidation rather than glycolysis as compared to lean mice, as assessed by metabolomic profiling. The improved efficacy of metformin in obesity corresponded with inhibition of mitochondrial complex 1 and fatty acid oxidation, and stimulation of glycolysis in only the OCs of obese versus lean mice. In conclusion, metformin had anti-tumorigenic effects in OC cell lines and the KpB OC pre-clinical mouse model, with increased efficacy in obese versus lean mice. Detected metabolic changes may underlie why ovarian tumors in obese mice have heightened susceptibility to metformin.en
dc.description.notesThis work is supported by a Department of Defense/Ovarian Cancer Research Program (DOD/OCRP), the Steelman Fund, and Translational Pilot Award (OC110163).en
dc.description.sponsorshipDepartment of Defense/Ovarian Cancer Research Program (DOD/OCRP); Steelman Fund; Translational Pilot Award [OC110163]en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.18632/oncotarget.20754en
dc.identifier.eissn1949-2553en
dc.identifier.issue67en
dc.identifier.pmid29340030en
dc.identifier.urihttp://hdl.handle.net/10919/93738en
dc.identifier.volume8en
dc.language.isoenen
dc.rightsCreative Commons Attribution 3.0en
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/en
dc.subjectmetforminen
dc.subjectmetabolismen
dc.subjectovarian canceren
dc.subjectmTOR pathwayen
dc.subjectObesityen
dc.titleIncreased efficacy of metformin corresponds to differential metabolic effects in the ovarian tumors from obese versus lean miceen
dc.title.serialOncotargeten
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.dcmitypeStillImageen

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