PLK1-mediated PDCD4 degradation confers resistance to enzalutamide in prostate cancer

Enzalutamide, a second-generation androgen receptor inhibitor, is utilized for treating patients with metastatic castration-resistant prostate cancer (mCRPC). However, acquired resistance to enzalutamide presents a significant clinical challenge, necessitating novel strategies for overcoming this resistance. In this study, we demonstrated that PLK1 phosphorylates PDCD4 at serine 239 (S239), leading to PDCD4 degradation by enhancing its binding to βTRCP2, thereby promoting enzalutamide resistance both in vitro and in vivo. Mechanistically, phosphorylation of PDCD4 at S239 upregulates the expression of UDP-glucuronosyltransferase 2B15 (UGT2B15) through activation of the c-MYC-Hedgehog axis. This pathway circumvents the androgen receptor, thereby reducing cellular sensitivity to enzalutamide treatment. Inhibition of UGT2B15 enhances enzalutamide-induced cell apoptosis and growth arrest in a manner dependent on PDCD4-S239 phosphorylation. Our findings provide a insight into the role of PLK1-mediated PDCD4 phosphorylation in enzalutamide resistance and suggest a potential therapeutic strategy to overcome resistance in prostate cancer.