The development of a novel therapeutic strategy for the treatment of prostate cancer by targeting metabolic signalling

Prostate cancer is one of the most prevalent cancers worldwide. The early stages of prostate cancer (PCa) are highly dependent on the androgen receptor (AR) pathway and hence therapies target this signalling axis. This approach is successful initially but invariably fails and the tumours progress to castration resistant prostate cancer (CRPC), for which few therapeutic options exist. Therefore, there is a great need to identify and characterize novel therapeutic targets for this stage of the disease. Cancer cells undergo alterations that allow them to survive and proliferate, and metabolic reprogramming is one of the most important manifestations in cancer progression. Therefore, targeting tumour metabolism is an attractive approach to treat cancer. Screening for novel metabolic targets was performed using an siRNA library. 26 metabolic factors were identified to affect proliferation and/or migration, and these were found to be involved in essential pathways including lipogenesis, heme-biosynthesis, redox homeostasis, and glycolysis. The lead targets were validated in a range of cell lines and additional assays performed to investigate the effect upon cell cycle and cell death. UROS, the fourth step of heme synthesis, was further investigated and depletion of this enzyme significantly inhibited prostate cancer proliferation and migration, promoted cell cycle arrest and induced cell death. Further, inhibition of heme synthesis using the inhibitor succinylacetone was found to significantly induce caspase-independent cell death and to sensitise cells to ROS. Importantly, the inhibitory activity of succinylacetone in combination with ROS showed specificity for cancer cell lines. Targeting heme synthesis therefore represents a novel targeted treatment option for prostate cancer and further work is needed to develop this into a therapeutic strategy