The study of a novel CDK8 inhibitor E966-0530-45418 that inhibits prostate cancer metastasis in vitro and in vivo
Journal
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Journal Volume
162
Pages
114667
Date Issued
2023-06
Author(s)
Ho, Tai-Yuan
Sung, Ting-Yi
Pan, Shiow-Lin
Huang, Wei-Jan
Hsu, Kai-Cheng
Hsu, Jui-Yi
Lin, Tony Eight
Hsu, Chia-Ming
Abstract
Prostate cancer is a prevalent malignancy among men globally, and androgen deprivation therapy is the conventional first-line treatment for metastatic prostate cancer. While androgen deprivation therapy is efficacious in castration-sensitive prostate cancer, it remains less effective in castration-resistant cases. Transcriptional dysregulation is a well-established hallmark of cancer, and targeting proteins involved in transcriptional regulation, such as cyclin-dependent kinase 8 (CDK8), has become an attractive therapeutic strategy. CDK8, a nuclear serine-threonine kinase, is a key component of the mediator complex and plays a critical role in transcriptional regulation. Recent studies have highlighted the promising role of CDK8 as a target in the treatment of metastatic prostate cancer. Our study assessed the efficacy of a novel CDK8 inhibitor, E966-0530-45418, which exhibited potent CDK8 inhibition (IC50 of 129 nM) and high CDK8 selectivity. Treatment with E966-0530-45418 significantly inhibited prostate cancer cell migration and epithelial-to-mesenchymal transition (EMT) at both the RNA and protein levels. Further mechanistic analysis indicated that E966-0530-45418 suppresses prostate cancer metastasis by decreasing CDK8 activity and inhibiting TGF-β1-mediated Smad3/RNA polymerase II linker phosphorylation and Akt/GSK3β/β-catenin signaling. The results in animal model also showed that E966-0530-45418 exhibited anti-metastatic properties in vivo. Our study demonstrated that E966-0530-45418 has great therapeutic potential in the treatment of metastatic prostate cancer.
Subjects
Cyclin-dependent kinase 8; Epithelial-to-mesenchymal transition; Mediator complex; Metastasis; Prostate cancer
SDGs
Type
journal article