PLCε knockdown overcomes drug resistance to androgen receptor antagonist in castration-resistant prostate cancer by suppressing the wnt3a/-catenin pathway

Most prostate cancers (Pcas) develop into castration-resistant prostate cancer (CRPC) after receiving androgen deprivation therapy (ADT). The expression levels of PLC epsilon and wnt3a are increased in Pca and regulate androgen receptor (AR) activity. However, the biological function and mechanisms of PLC epsilon and wnt3a in CRPC remain unknown. In this study, we found that the expression levels of PLC epsilon, wnt3a, and AR were significantly increased in CRPC tissues as well as bicalutamide-resistant-LNCaP and enzalutamide-resistant-LNCaP cells. In addition, PLC epsilon knockdown partly restored the sensitivity of drug-resistant cells to bicalutamide and enzalutamide by inhibiting the activity of the wnt3a/-catenin/AR signaling axis. Interestingly, the resistance of LNCaP cells docetaxel is related to PLC epsilon but not the wnt3a/-catenin pathway. We also found that the combination of PLC epsilon knockdown and enzalutamide treatment synergistically suppressed cell proliferation, tumor growth, and bone metastasis using in vitro and in vivo experiments. Our study revealed that PLC epsilon is involved in the progression of drug-resistance in CRPC and could be a new target for the treatment of CRPC.