The kinase PLK1 promotes Hedgehog signaling-dependent resistance to the antiandrogen enzalutamide in metastatic prostate cancer.

ABSTRACT: Enzalutamide, a second-generation androgen receptor inhibitor (also known as an antiandrogen), is used to treat patients with metastatic castration-resistant prostate cancer (CRPC). Tumors often acquire resistance to enzalutamide. Tumor progression and enzalutamide resistance are associated with decreased abundance of the tumor suppressor PDCD4. In normal dividing cells, PDCD4 abundance is low when that of the kinase PLK1 is high. In this study, we found that PLK1 acted on PDCD4 to promote enzalutamide resistance in CRPC cells in culture and in mice via a mechanism that revealed an effective combination therapy. PLK1 phosphorylated PDCD4 at Ser²³⁹, leading to its degradation and consequently inducing the transcriptional activation of Hedgehog (Hh) signaling by c-MYC. Hh signalin

SUBMITTER: Zhang Q 

PROVIDER: S-EPMC11988940 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature