Endocrine Abstracts (2016) 40 P25 | DOI: 10.1530/endoabs.40.P25

Metformin suppressed the proliferation of prostate cancer cells in vitro and reduced prostate tumor growth in vivo under low-fat and, especially, under high-fat fed conditions

André Sarmento-Cabral, Fernando López-López, Justo P Castaño & Raúl M Luque


Department of Cell Biology, Physiology and Immunology, University of Córdoba; Hospital Universitario Reina Sofía, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC); CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn); and, Campus de Excelencia Internacional Agroalimentario (ceiA3), Córdoba, Spain.


Obesity (Ob) is a chronic endocrine-metabolic disease and one of the most serious and complex threats for the human health, which is associated with an increased incidence of some types of cancers such as prostate cancer (PC), the second most common cancer in men worldwide. Interestingly, metformin (Met), an antidiabetic drug, might represents a very promising opportunity to treat Ob and PC as some retrospective clinical studies have shown that the incidence of PC is lower in patients treated with Met. However, the endocrine-metabolic, cellular and molecular mechanisms underlying the association between Ob and higher incidence/aggressiveness of PC and the putative pharmacological effectiveness of Met in PC are still unknown. We used primary normal prostate (NP) cell cultures from mice and human PC cell lines (PC3, 22Rv1 and LNCaP) as well as, immuno-suppressed mice inoculated with PC3 cells, fed a high-fat diet (HFD) or low-fat diet (LFD), as models to test the beneficial effect of Met (doses used: in vitro (10 μM–10 mM) or, in vivo (250 mg/Kg per day)). Our results indicate that Met modulates key metabolic, endocrine and pathologic components (e.g. expression of different components of insulin/IGF-I/somatostatin/ghrelin systems) in NP cell cultures. Interestingly, Met had no evident effect on 22Rv1 cells proliferation but significantly reduced PC3 and LNCaP cells proliferation and/or migration. Remarkably, we found that Met also have a significant beneficial in vivo effect as it reduced tumor volume and weight in mice fed a LFD and, specially, on those fed a HFD compared to their vehicle-treated control mice. In line with this, Met regulated the expression of key markers involved in cellular proliferation (i.e. PTTG and p53) and glucose/insulin homeostasis (i.e. IRS and AKT isoforms, IGFIBP3 and receptors for insulin, IGFI and GH) in tumors of mice fed a LFD and/or a HFD. In addition, Met significantly decreased the percentage of tumor cells mitosis and tumor necrosis under HFD, but not LFD, conditions and tends to activate ERK signaling (increased p-ERK/total-ERK; P=0.09), but not AKT signaling, only in tumors of mice fed a HFD. Altogether, our data suggest that Met modulates NP cell function and exerts beneficial effects in the inhibition of PC cells growth in vitro and in vivo, specially, under HF-conditions.

Funding: PI13-00651, BFU2013-43282-R, BIO-0139, CTS-1406, PI-0639-2012, and CIBERobn.

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