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Published on: October 30, 2013
CK1δ as a potential therapeutic target to treat bladder cancer
Yu-Chen Lin1, Mei-Chuan Chen2,3, Tsung-Han Hsieh4
1Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
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.
Insights
A novel compound, 13i HCl, effectively inhibits bladder cancer progression by targeting CK1δ (Casein Kinase 1 delta). This potent inhibitor reduces tumor growth, induces cell death, and blocks cancer cell migration, offering a promising new therapeutic avenue.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Bladder cancer is a prevalent genitourinary malignancy with limited advanced treatment options.
- Current therapies for advanced bladder cancer include immune-checkpoint inhibitors and erdafitinib.
- 13i HCl, a potent CK1δ inhibitor, demonstrated significant anti-bladder cancer activity in prior research.
Purpose of the Study:
- To elucidate the pharmacological mechanisms of 13i HCl in inhibiting human bladder cancer.
- To investigate the role of CK1δ (Casein Kinase 1 delta) in bladder cancer progression.
- To evaluate the therapeutic potential of 13i HCl for bladder cancer treatment.
Main Methods:
- Analysis of CSNK1D gene expression in bladder cancer patient datasets.
- Assessment of CK1δ knockdown effects on bladder cancer cell growth and β-catenin expression.
- In vitro evaluation of 13i HCl and PF-670462 on bladder cancer cell proliferation, apoptosis, necroptosis, and migration.
Main Results:
- CSNK1D gene expression is upregulated in superficial and infiltrating bladder cancer.
- CK1δ knockdown reduced β-catenin and inhibited bladder cancer cell growth.
- 13i HCl suppressed proliferation, increased apoptosis, induced necroptosis, and inhibited migration in bladder cancer cells.
Conclusions:
- 13i HCl effectively inhibits bladder cancer through multiple mechanisms, including targeting CK1δ.
- The study highlights the upregulation of CSNK1D in bladder cancer, suggesting CK1δ as a therapeutic target.
- 13i HCl shows promise as a potential therapeutic agent for advanced bladder cancer, warranting further development.
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