Dinaciclib exerts a tumor-suppressing effect via β-catenin/YAP axis in pancreatic ductal adenocarcinoma.

Abstract

Dinaciclib, a cyclin-dependent kinase-5 (CDK5) inhibitor, has significant anti-tumor properties. However, the precise mechanism of dinaciclib requires further investigation. Herein, we investigated the anti-tumor functions and molecular basis of dinaciclib in pancreatic ductal adenocarcinoma (PDAC). PDAC and matched para-carcinoma specimens were collected from the patients who underwent radical resection. Immunohistochemistry was performed to assess CDK5 expression. Cell proliferation ability, migration, and invasion were measured using Cell Counting Kit-8, wound healing, and transwell assay, respectively. The cell cycle and apoptosis were assessed using flow cytometry. Gene expression was examined using RNA-seq and quantitative real-time PCR. Protein expression of proteins was measured by western blot analysis and immunofluorescence microscopy. Tumor-bearing mice were intraperitoneally injected with dinaciclib. CDK5 is highly expressed in PDAC. The expression level of CDK5 was significantly related to tumor size, T stage, and the American Joint Committee on Cancer stage. High CDK5 expression can predict poor survival in PDAC patients. In addition, the expression level of CDK5 might be an independent prognostic factor for PDAC patients. Dinaciclib inhibits the growth and motility of PDAC cells and induces apoptosis and cell cycle arrest in the G2/M phase. Mechanistically, dinaciclib down-regulated yes-associated protein (YAP) mRNA and protein expression by reducing β-catenin expression. Moreover, dinaciclib significantly inhibited PDAC cell growth in vivo . Our findings reveal a novel anti-tumor mechanism of dinaciclib in which it decreases YAP expression by down-regulating β-catenin at the transcriptional level rather than by activating Hippo pathway-mediated phosphorylation-dependent degradation.

• Authors: Yichen Li, Zhenjiang Zheng, Li Xiao, Yonghua Chen, Xubao Liu, Dan Long, Li Chai, Yi Li, Chunlu Tan
• Journal: Anti-cancer drugs (Anticancer Drugs) Vol. 35 Issue 2 Pg. 140-154 (02 01 2024) ISSN: 1473-5741 [Electronic] England
• PMID: 37694833 (Publication Type: Journal Article)
• Copyright: Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.

Chemical References

• beta Catenin
• dinaciclib
• Catenins

Topics

• Humans
• Mice
• Animals
• beta Catenin (metabolism)
• Catenins (genetics, metabolism, pharmacology)
• Pancreatic Neoplasms (drug therapy, genetics, metabolism)
• Carcinoma, Pancreatic Ductal (drug therapy, genetics, metabolism)
• Cell Proliferation
• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic
• Cell Movement