Chalcone Derivatives Suppress Proliferation and Migration of Castration-resistant Prostate Cancer Cells Through FAK-mediated DNA Damage.

Abstract

Castration-resistant prostate cancer (CRPC) contributes to the deaths of most men from prostate cancer. Focal adhesion kinase (FAK) is abnormally up-regulated in CRPC. Chalcone possesses potent anticancer activity with clinical potential. However, it remains unknown whether its derivatives can be exploited as promising oncotherapeutic agents in CRPC treatment by inhibiting FAK-related signaling pathway. This study aimed to investigate the anticancer effects and the underlying mechanisms of action of chalcone derivatives against CRPC cells. Two chalcone derivatives (compounds 1 and 2) were synthesized, and their anti-CRPC activity toward DU145 and PC3 cells was evaluated. The effect of chalcone derivatives on CRPC cells was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, colony-formation, 5-ethynyl-2'-deoxyuridine staining, flow cytometric, cell adhesion and transwell assays. The study of mechanisms was conducted through comet, immunofluorescence and western blot assay, analysis of The Cancer Genome Atlas and molecular docking. The results revealed that both compounds exhibited stronger cytotoxicity to CRPC cells along with significant inhibition of colony formation, especially compound 1 Further experimental evidence indicated that 1 significantly inhibited DNA replication, induced cell-cycle arrest and cell apoptosis. Additionally, treatment with 1 inhibited cell-matrix adhesion and migration of CRPC cells. Mechanistically, the results suggest that 1 inhibited FAK expression and phosphorylation, as well as affected its distribution, resulting in intense DNA damage and strong DNA damage response. We discovered two chalcone derivatives and collective results indicated that 1 inhibited CRPC cell proliferation and migration through FAK-mediated DNA damage and may be a potential therapeutic drug against CRPC.