期刊
AGING-US
卷 12, 期 7, 页码 5764-5780出版社
IMPACT JOURNALS LLC
DOI: 10.18632/aging.102966
关键词
bladder cancer; CK1 delta; apoptosis; necroptosis; migration
资金
- Ministry of Science and Technology of the Republic of China [MOST-107-2320-B-038-039]
- TMU Research Center of Cancer Translational Medicine from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan
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 CK1 delta 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 CK1 delta, is upregulated in superficial and infiltrating bladder cancer patients in two independent datasets. CK1 delta knockdown decreased beta-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 CK1 delta 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.
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