Introduction: Prostate cancers (PCa) exhibit a unique metabolic profile with reliance on different forms of glucose metabolism at different stages of disease progression. Early stage PCa cells use the more efficient TCA cycle, while metastatic PCa cells switch to glycolysis (Warburg effect), leading to the accumulation of lactate. Monocarboxylate transporters (MCTs) play a major role in the export/import of lactate to maintain redox balance. Such metabolic reprogramming can lead to gain-of-function mutations and affect drug sensitivity. MCT expression levels are high in enzalutamide-resistant PCa cells. Hence, we hypothesized that MCT inhibition may be an attractive therapeutic strategy to overcome enzalutamide resistance in PCa cells. Methods: We analyzed the expression levels of MCTs in PCa tissues using public datasets from Oncomine. We treated C4-2B and 22Rv1 parental and enzalutamide-resistant cells with varying concentrations of MCT inhibitors AR-C155858, AZD3965, or syrosingopine either singly or in combination with enzalutamide and assessed cell survival, cell viability, proliferation, clonogenic ability, survival in 3-D models, and glycolytic activity. We treated mouse xenografts of PCa cells with MCT inhibitors or enzalutamide either singly or in combination and assessed tumor growth. Results: We found that the suppression of MCT activity using the MCT antagonists AR-C155858, AZD3965, or syrosingopine significantly diminished the proliferation, survival, and clonogenic ability of enzalutamide-resistant PCa cells compared with parental cells. MCT inhibition in combination with enzalutamide inhibited the metabolic adaptation of PCa cells. Tumor growth of enzalutamide-resistant PCa cell xenografts was suppressed significantly when treated with a combination of MCT inhibitors with enzalutamide. These findings imply that MCT inhibition may be an effective strategy to counter enzalutamide resistance in PCa. Conclusions: MCT activation may underlie the development of enzalutamide resistance in PCa and targeting it may represent a viable combinatorial option. SOURCE OF Funding: Department of Defense Prostate Prostate Cancer Research Program W81XWH2010794 (PC190332)
