title: Metformin Reduces Prostate Tumor Growth, in a Diet-Dependent Manner, by Modulating Multiple Signaling Pathways.
abstract: Prostate-cancer is strongly influenced by obesity, wherein metformin could represent a promising treatment; however, the endocrine metabolic/cellular/molecular mechanisms underlying these associations and effects are still unclear. To determine the beneficial antitumoral effects of metformin on prostate cancer progression/aggressiveness and the relative contribution of high-fat diet (HFD; independently of obesity), we used HFD-fed immunosuppressed mice inoculated with PC3 cells (which exhibited partial resistance to diet-induced obesity) compared with low-fat diet (LFD)-fed control mice. Moreover, gene expression analysis was performed on cancer-associated genes in the xenografted tumors, and the antitumorigenic role of metformin on tumoral (PC3/22Rv1/LNCaP) and normal (RWPE1) prostate cells was evaluated. The results demonstrate that HFD is associated with enhanced prostate cancer growth irrespective of body weight gain and endocrine metabolic dysregulations and that metformin can reduce prostate cancer growth under LFD but more prominently under HFD, acting through the modulation of several tumoral-associated processes (e.g., cell cycle, apoptosis, and/or necrosis). Moreover, the actions observedin vivocould be mediated by the modulation of the local expression of GH/IGF1 axis components. Finally, it was demonstrated that metformin had disparate effects on proliferation, migration, and prostate-specific antigen secretion from different cell lines. Altogether, these data reveal that metformin inhibits prostate cancer growth under LFD and, specially, under HFD conditions through multiple metabolic/tumoral signaling pathways.Implications:The current study linking dietary influence on metformin-regulated signaling pathways and antitumoral response provides new and critical insight on environment-host interactions in cancer and therapy.Mol Cancer Res; 15(7); 862-74. ©2017 AACR.
authors.affiliation: Maimonides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, Spain.|Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain.|Reina Sofia University Hospital (HURS), Córdoba, Spain.|CIBERobn, Madrid, Spain.|ceiA3, Córdoba, Spain.
authors.forename: André
authors.initials: A
authors.lastname: Sarmento-Cabral
authors.affiliation: Maimonides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, Spain.|Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain.|Reina Sofia University Hospital (HURS), Córdoba, Spain.|CIBERobn, Madrid, Spain.|ceiA3, Córdoba, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: L-López
authors.affiliation: Maimonides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, Spain.|Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain.|Reina Sofia University Hospital (HURS), Córdoba, Spain.|CIBERobn, Madrid, Spain.|ceiA3, Córdoba, Spain.
authors.forename: Manuel D
authors.initials: MD
authors.lastname: Gahete
authors.affiliation: Maimonides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, Spain.|Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain.|Reina Sofia University Hospital (HURS), Córdoba, Spain.|CIBERobn, Madrid, Spain.|ceiA3, Córdoba, Spain.
authors.forename: Justo P
authors.initials: JP
authors.lastname: Castaño
authors.affiliation: Maimonides Institute of Biomedical Research of Córdoba (IMIBIC), Córdoba, Spain. raul.luque@uco.es.|Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain.|Reina Sofia University Hospital (HURS), Córdoba, Spain.|CIBERobn, Madrid, Spain.|ceiA3, Córdoba, Spain.
authors.forename: Raúl M
authors.initials: RM
authors.lastname: Luque
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D018752:Diet, Fat-Restricted; D059305:Diet, High-Fat; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D008297:Male; D008687:Metformin / Q000008:administration & dosage*; D051379:Mice; D009765:Obesity; D011467:Prostate / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: C583557:IGF1 protein, human; D007334:Insulin-Like Growth Factor I; D008687:Metformin