The Mechanism Of Action Of Sinularin Inhibits Prostate Cancer Growth And Metastasis

Objective:Prostate cancer is the second-leading cause of cancer death in men.Sinularin is a natural compound extracted from soft corals that has anticancer activity in many cancer cells.However,the pharmacological mechanism of actions of Sinularin in prostate cancer is unclear.The aim of the study is to examine the anticancer effects of sinularin in prostate cancer cells.Methods:This study was to investigate the anti-cancer mechanism of actions of Sinularin on prostate cancer cell lines PC3、DU145 and LNCa P.MTT assay was used to detect the effect of Sinularin on the cell viability of prostate cancer cells in the presence or absence of apoptosis inhibitor Z-VAD-FMK.The effect of Sinularin on the colony formation ability of prostate cancer cells was detected by colony formation assay.The effects of Sinularin on the migration and invasion of PC3 and DU145 were detected by wound healing assay and Transwell assay.Western Blot was used to detect the effect of Sinularin on protein expression in prostate cancer cells in the presence or absence of testosterone or transforming Growth Factor-β1(TGF-β1).Reactive Oxygen Species(ROS)and glutathione(GSH)kits were used to detect the changes of lipid reactive oxygen species and glutathione content in prostate cancer cells under Sinularin treatment with or without ferroptosis inhibitor ferrostatin-1.Results:Sinularin can inhibit the cell viability and colony formation of prostate cancer cells.In addition,Sinularin inhibited androgen-induced LNCa P cell growth by down-regulating the protein expression levels of androgen receptor(AR),5α-reductase type II and prostate-specific antigen(PSA).In the presence or absence of TGF-β1 treatment,Sinularin significantly reduced the invasion and migration of PC3 and DU145 cells.By up-regulating the expression of E-cadherin protein and down-regulating the protein expression of N-cadherin and vimentin,Sinularin inhibits the process of epithelial-mesenchymal transition(EMT)of DU145 cells after 48 h treatment.Sinularin can induce autophagy by up-regulating the protein expression levels of Beclin-1 and LC3 B.Sinularin can also induce ferroptosis and apoptosis of prostate cancer cells by regulating the protein expression levels of NRF2,GPX4,PARP,Caspase-3,Caspase-7,Caspase-9,Cleaved-PARP,Bcl-2 and Bax.After Sinularin treatment,ROS content was significantly increased and GSH content was decreased in PC3,DU145 and LNCa P prostate cancer cells.Conclusion:Sinularin regulates androgen receptor signaling pathway and induces apoptosis,autophagy and ferroptosis in prostate cancer cells.In summary,Sinularin can be considered as a therapeutic drug for human prostate cancer.