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 anti-tumoral effects of metformin on prostate-cancer progression/aggressiveness and the relative contribution of high-fat diet (HFD; independently of obesity), we used HFD-fed immuno-suppressed 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 anti-tumorigenic role of metformin on tumoral (PC3/22Rv1/LNCaP) and normal (RWPE1) prostate cells was evaluated. The results demonstrate that HFD is associates with enhanced prostate-cancer growth irrespective of body-weight gain and endocrine-metabolic dysregulations and that metformin can reduce prostate-cancer a 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 observed in vivo could 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 PSA 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 anti-tumoral response provides new and critical insight on environment-host interactions in cancer and therapy.
- Received December 28, 2016.
- Revision received March 28, 2017.
- Accepted March 30, 2017.
- Copyright ©2017, American Association for Cancer Research.