Gut microbiota-derived short-chain fatty acids promote prostate cancer progression through inducing cancer cell autophagy and M2 macrophage polarization

Abstract

Abstract Objective: Emerging research have reported the regulative role of gut microbiota-derived short-chain fatty acids (SCFAs) within tumor microenvironment. In previous study we have demonstrated abnormal gut microbial composition in castration-resistant prostate cancer (CRPC) patients, here we sought to reveal the mechanism of SCFAs as a mediator linking microbiota dysbiosis and prostate cancer (PCa) progression. Methods:By using transgenic TRAMP mouse model, PCa patient samples, in vitro PCa cell transwell assay, and macrophage recruitment assay, we examined the effects of fecal microbiota transplantation (FMT) and SCFAs on PCa progression. Results: FMT using CRPC patients’ fecal suspension increased the abundance of SCFAs-producing gut microbiotas in TRAMP mice including Ruminococcus, Alistipes, Phascolarctobaterium, and correspondingly raised mice’s gut acetate and butyrate levels. CRPC FMT or SCFAs supplementation accelerated TRAMP mice’s cancer progression. In vitro, SCFAs enhanced PCa cells migration and invasion by inducing TLR3-triggered autophagy that further activated NF-κB and MAPK signalings. Also, PCa cell-derived CCL20 activated by SCFAs reprogrammed the tumor microenvironment by recruiting more macrophage infiltration and simultaneously inducing M2 macrophage polarization, which in turn further strengthened PCa cells invasiveness. Finally in a large cohort of 362 PCa patients from our department, we demonstrated that CCL20 expression in prostate was positively correlated with Gleason grade, pre-operative PSA, neural invasion, seminal vesical invasion, and was negatively correlated with post-operative biochemical recurrence-free survival. Gut microbiota dysbiosis-related CCL20 could be a biomarker for predicting prognosis in PCa patients. Conclusion: Collectively, gut microbiota dysbiosis-derived SCFAs promoted PCa progression through inducing cancer cell autophagy and M2 macrophage polarization. Intervention of SCFAs-producing microbiotas may be a useful strategy in the manipulation of CRPC.