The Study Of Anti-tumor Effects And Underlying Mechanism Of Proscillaridin A On The Prostate Cancer

Objective:Prostate cancer(PCa)is the second commonly diagnosed malignancy in men over the world.Although androgen deprivation therapy for advanced PCa patients has significantly improved their survival,the majority of these patients eventually develop castration-resistant prostate cancer(CRPC)and become dependent on chemotherapy to prolong live.(Pro A),a cardiac glycoside that is clinically used to treat various heart failure diseases,has been reported to have anticancer activity in several cancers.However,whether Pro A exerts an inhibitory effect on PCa progression remains unknown.In this study,we determined possible anti-tumor effects and underlying mechanism of Pro A on PCa cells.Methods: The effect of Pro A on PCa cells was assessed by cell viability,colony formation,cell apoptosis,TUNEL staining.Besides wound-healing,migration and invasion assays were used to assessed the effect on metastatic potential of PCa cells.Xenograft and patient-derived organoid model were further used to assessed the effect of Pro A on PCa cells.RNA-sequencing analysis and Gene set enrichment analysis(GSEA)was used to find underlying mechanism and confirmed via real-time PCR,western blot assays and immunofluorescence analysis.Results: Pro A inhibits proliferation,migration,and invasion of PCa cells and induces cell apoptosis in vitro.In addition,we also show that Pro A possesses an inhibitory effect in PC3 xenografts and patient-derived organoids(PDOs)models.Furthermore,Pro A shows an enhanced inhibitory effect on PCa cell growth when combined with docetaxel.Our data show that Pro A drives the execessive activation of the UPR signaling and inhibits the activity of Wnt signaling on prostate cancer cell.Conclusion: Pro A impedes PCa cell growth,induces cell apoptosis of PCa cells in vitro and in vivo.Tumor growth-inhibitory effects of Pro A is achieved via driving the activation of UPR signaling and inhibiting the activity of Wnt signaling.Besides,Pro A reduces the growth of patient-derived organoids.