Treatments for advanced prostate cancer (PCa) continue to target androgen signalling leading to prolonged androgen deprivation. A major side-effect of androgen deprivation is development of insulin resistance resulting in hyperinsulinaemia, which is specifically associated with more rapid progression and increased cancer mortality, but is not clinically addressed. Metformin is used widely in the treatment of diabetes and insulin resistance but its effects in cancer cells has been shown to be dependent on cancer type and context. We examined the effect of metformin, in androgen-deprived PCa cells, utilising the androgen-dependent LNCaP and DUCaP cell lines, and the novel castrate-resistant cell line, MSK3.
Microarray of LNCaP cells +/-10nM DHT, +/- 5mM metformin followed by Ingenuity pathway analysis identified apoptosis and autophagy pathways modulated by metformin. QRT-PCR revealed Bcl2, Bcl-XL and ATG12, upregulated by androgens, were dose-dependently downregulated by metformin in all cell lines. Increased rates of apoptosis with metformin treatment, measured by FACS accompanied decreases in autophagy, using CYTO-ID stain. Androgen deprivation was associated with a 15% reduction in maximal mitochondrial respiration, which was restored with 10nM DHT. Metformin dose-dependently reduced mitochondrial activity, which was accompanied by an overall decreased glycolytic capacity. Our results suggest metformin counteracts survival pathways in androgen-deprived PCa cells. These results suggest a susceptibility of PCa cells to metformin, irrespective of androgen dependence. In a parallel randomised, placebo-controlled clinical trial, we have observed that metformin prevents ADT-induced metabolic deterioration in men with newly diagnosed metastatic disease, including improved fasting insulin and HOMA, which supports its use as adjuvant therapy with androgen deprivation.