High dose androgen suppresses natural killer cytotoxicity of castration-resistant prostate cancer cells via altering AR/circFKBP5/miRNA-513a-5p/PD-L1 signals

Most advanced prostate cancer (PCa) patients initially respond well to androgen deprivation therapy, but almost all eventually develop castration-resistant prostate cancer (CRPC). Early studies indicated the bipolar androgen therapy via a cycling of high dose and low dose of androgen to suppress PCa growth might be effective in a select patient population. The detailed mechanisms, however, remain unclear. Here we found the capacity of natural killer (NK) cells to suppress the CRPC cells could be suppressed by a high dose of dihydrotestosterone (DHT). Mechanism dissection indicates that transactivated AR can increase circularRNA-FKBP5 (circFKBP5) expression, which could sponge/inhibit miR-513a-5p that suppresses the PD-L1 expression via direct binding to its 3MODIFIER LETTER PRIMEUTR to negatively impact immune surveillance from NK cells. Preclinical data from in vitro cell lines and an in vivo mouse model indicate that targeting PD-L1 with sh-RNA or anti-PD-L1 antibody can enhance the high dose DHT effect to better suppress CRPC cell growth. These findings may help us to develop novel therapies via combination of high dose androgen with PD-1/PD-L1 checkpoint inhibitors to better suppress CRPC progression.

Automated summary

In castration-resistant prostate cancer (CRPC), high dose dihydrotestosterone (DHT) suppresses the ability of natural killer (NK) cells to inhibit CRPC cells and negatively impacts immune surveillance. Mechanistically, DHT transactivates AR to increase circularRNA-FKBP5 (circFKBP5) expression, which inhibits miR-513a-5p and increases PD-L1 expression. Targeting PD-L1 enhances the suppressive effect of high dose DHT on CRPC cell growth.