https://scholars.lib.ntu.edu.tw/handle/123456789/634517
Title: | The study of a novel CDK8 inhibitor E966-0530-45418 that inhibits prostate cancer metastasis in vitro and in vivo | Authors: | Ho, Tai-Yuan Sung, Ting-Yi Pan, Shiow-Lin Huang, Wei-Jan Hsu, Kai-Cheng Hsu, Jui-Yi Lin, Tony Eight Hsu, Chia-Ming CHIA-RON YANG |
Keywords: | Cyclin-dependent kinase 8; Epithelial-to-mesenchymal transition; Mediator complex; Metastasis; Prostate cancer | Issue Date: | Jun-2023 | Journal Volume: | 162 | Start page/Pages: | 114667 | Source: | Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie | 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. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/634517 | ISSN: | 07533322 | DOI: | 10.1016/j.biopha.2023.114667 |
Appears in Collections: | 藥學系 |
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