Research Paper Volume 12, Issue 7 pp 5764—5780
CK1δ as a potential therapeutic target to treat bladder cancer
- 1 Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- 2 Ph.D. Program in Clinical Drug Development of Herbal Medicine, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
- 3 Traditional Herbal Medicine Research Center of Taipei Medical University Hospital, Taipei, Taiwan
- 4 Joint Biobank, Office of Human Research, Taipei Medical University, Taipei, Taiwan
- 5 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
- 6 Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
- 7 TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan
Received: November 16, 2019 Accepted: January 27, 2020 Published: April 13, 2020
https://doi.org/10.18632/aging.102966How to Cite
Copyright © 2020 Lin et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Bladder cancer is the second most common genitourinary malignancy in the world. However, only immune-checkpoint inhibitors and erdafitinib are available to treat advanced bladder cancer. Our previous study reported that 4-((4-(4-ethylpiperazin-1-yl) phenyl)amino)-N-(3,4,5-trichlorophenyl)-7H-pyrrolo-[2, 3-d]pyrimidine-7-carboxamide hydrochloride (13i HCl) is a potent CK1δ inhibitor showing significant anti-bladder cancer activity. In this study, we elucidated the pharmacological mechanisms underlying 13i HCl’s inhibition of human bladder cancer. Our results demonstrate that expression of the CSNK1D gene, which codes for CK1δ, is upregulated in superficial and infiltrating bladder cancer patients in two independent datasets. CK1δ knockdown decreased β-catenin expression in bladder cancer cells and inhibited their growth. Additionally, 13i HCl suppressed bladder cancer cell proliferation and increased apoptosis. We also observed that inhibition of CK1δ using 13i HCl or PF-670462 triggers necroptosis in bladder cancer cells. Finally, 13i HCl inhibited bladder cancer cell migration and reversed their mesenchymal characteristics. These findings suggest further development of 13i HCl as a potential therapeutic agent to treat bladder cancer is warranted.
Abbreviations
BC: bladder cancer; EMT: epithelial-mesenchymal transition; MIBC: muscle invasive bladder cancer; MTSS1: metastasis suppressor 1; NMIBC: non-muscle invasive bladder cancer; PCD: programmed cell death; ROS: reactive oxygen species.