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

IF 6.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling Pub Date : 2025-03-18 DOI:10.1126/scisignal.adi5174

Qiongsi Zhang, Jia Peng, Yanquan Zhang, Jinghui Liu, Daheng He, Yue Zhao, Xinyi Wang, Chaohao Li, Yifan Kong, Ruixin Wang, Fengyi Mao, Chi Wang, Qing Wang, Min Zhang, Jianlin Wang, Hsin-Sheng Yang, Xiaoqi Liu

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引用次数: 0

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 signaling supports tumor cell proliferation and stemness by inducing the enzyme UDP-glucuronosyltransferase 2B15 (UGT2B15), which promotes the metabolic clearance of drugs and steroid hormones. Thus, this pathway may circumvent androgen receptor dependence, thereby reducing cellular sensitivity to enzalutamide. Knocking down UGT2B15 enhanced enzalutamide-induced cell apoptosis and growth arrest in a PDCD4-dependent manner. Combining enzalutamide with the clinically approved Hh pathway inhibitor vismodegib inhibited cell growth and promoted apoptosis in enzalutamide-resistant cell cultures and xenografts in vivo. Our findings reveal a mechanism of PLK1-mediated enzalutamide resistance and suggest a potential therapeutic strategy to overcome this resistance in prostate cancer.

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来源期刊

Science Signaling BIOCHEMISTRY & MOLECULAR BIOLOGY-CELL BIOLOGY

CiteScore

9.50

自引率

0.00%

发文量

148

审稿时长

3-8 weeks

期刊介绍： "Science Signaling" is a reputable, peer-reviewed journal dedicated to the exploration of cell communication mechanisms, offering a comprehensive view of the intricate processes that govern cellular regulation. This journal, published weekly online by the American Association for the Advancement of Science (AAAS), is a go-to resource for the latest research in cell signaling and its various facets. The journal's scope encompasses a broad range of topics, including the study of signaling networks, synthetic biology, systems biology, and the application of these findings in drug discovery. It also delves into the computational and modeling aspects of regulatory pathways, providing insights into how cells communicate and respond to their environment. In addition to publishing full-length articles that report on groundbreaking research, "Science Signaling" also features reviews that synthesize current knowledge in the field, focus articles that highlight specific areas of interest, and editor-written highlights that draw attention to particularly significant studies. This mix of content ensures that the journal serves as a valuable resource for both researchers and professionals looking to stay abreast of the latest advancements in cell communication science.