Abstract
BackgroundMetformin is an approved drug prescribed for diabetes. Its role as an anti-cancer agent has drawn significant attention because of its minimal side effects and low cost. However, its mechanism of anti-tumour action has not yet been fully clarified.MethodsThe effect on cell growth was assessed by cell counting. Western blot was used for analysis of protein levels, Boyden chamber assays for analyses of cell migration and co-immunoprecipitation (CoIP) followed by western blot, PCR or qPCR for analysis of protein-protein and protein-mRNA interactions.ResultsMetformin showed an anti-proliferative effect on a wide range of prostate cancer cells. It disrupted the AR translational MID1 regulator complex leading to release of the associated AR mRNA and subsequently to downregulation of AR protein in AR positive cell lines. Inhibition of AR positive and negative prostate cancer cells by metformin suggests involvement of additional targets. The inhibitory effect of metformin was mimicked by disruption of the MID1-α4/PP2A protein complex by siRNA knockdown of MID1 or α4 whereas AMPK activation was not required.ConclusionsFindings reported herein uncover a mechanism for the anti-tumor activity of metformin in prostate cancer, which is independent of its anti-diabetic effects. These data provide a rationale for the use of metformin in the treatment of hormone naïve and castration-resistant prostate cancer and suggest AR is an important indirect target of metformin.
Highlights
Metformin is an approved drug prescribed for diabetes
Metformin inhibits growth and reduces AR protein levels in prostate cancer cell lines The anti-proliferative effect of metformin has been reported for LNCaP, C4-2, PC-3, and Du-145 prostate cancer cell lines
In the AR positive cell lines, AR protein levels decreased upon metformin treatment in a dose-dependent manner (Figure 1D, E)
Summary
Metformin is an approved drug prescribed for diabetes. Its role as an anti-cancer agent has drawn significant attention because of its minimal side effects and low cost. A recent meta-analysis failed to find an influence of metformin on prostate cancer risk [3]. Despite these ambiguous data metformin inhibits many tumour cells in-vitro, including prostate cancer cells [4] and a number of clinical studies have been initiated to test the therapeutic efficacy of metformin in different cancer entities. Metformin reduces hepatic glucose production by inhibiting gluconeogenesis. This effect is mainly achieved via inhibition of the mitochondrial respiratory chain I complex. Activation of AMPK shifts cells from an anabolic to a catabolic state by inhibiting protein, glucose and lipid synthesis, and inducing glucose uptake by the glucose transporters GLUT1 and GLUT4 [7]
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