The study of a novel CDK8 inhibitor E966-0530–45418 that inhibits prostate cancer metastasis in vitro and in vivo - 29/04/23
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.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Highlights |
• | E966-0530–45418 inhibited CDK8 (IC50 of 129 nM) with high selectivity, reducing prostate cancer migration and EMT. |
• | E966-0530–45418 decreased CDK8 activity, inhibiting TGF-β1-mediated Smad3/RNA pol II phosphorylation and Akt/GSK3β/β-catenin signaling. |
• | E966-0530–45418 shows promise for treating metastatic prostate cancer. |
Keywords : Cyclin-dependent kinase 8, Mediator complex, Epithelial-to-mesenchymal transition, Metastasis, Prostate cancer
Plan
Vol 162
Article 114667- juin 2023 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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