Inhibition of Bruton's Tyrosine Kinase Suppresses Cancer Stemness and Promotes Carboplatin-induced Cytotoxicity Against Bladder Cancer Cells.

Abstract

Bruton's tyrosine kinase (BTK) has been discovered to serve a critical role in the survival and infiltration of B-cell lymphoma. Recently, it was reported that BTK inhibitors exerted potential beneficial effects against numerous types of solid tumor, including glioblastoma multiforme and breast cancer; however, whether BTK is crucial for the progression of bladder cancer (BLCA) remains unclear. The present study investigated the in vitro function of BTK in stemness properties of BLCA cells. Furthermore, the therapeutic effects of a standard chemotherapeutic drug, carboplatin in combination with the BTK inhibitor, ibrutinib were also investigated. The association between BTK and BLCA progression was evaluated using free databases. The in vitro stemness and metastatic properties of BLCA cells were also investigated. Finally, the cytotoxicity of carboplatin in combination with ibrutinib was determined. The meta-survival analysis of the association between BTK and BLCA progression revealed that the expression levels of BTK were associated with a higher risk of BLCA progression. The CD133+-side population of BLCA cells formed spheroids when cultured in serum-free conditioned medium. In addition, expression levels of BTK and activated mTOR signaling in side population cells was up-regulated compared with the parental BLCA cells. Furthermore, the transfection of short hairpin RNA targeting BTK into BLCA cells markedly reduced cell migratory ability. More importantly, in advanced BLCA cells, which were more resistant to carboplatin, it was discovered that the cell viability was significantly reduced in the presence of ibrutinib (p<0.05). The findings of the present study suggested that BTK may have a critical role in the progression of BLCA; however, the underlying mechanisms and potential therapeutic strategies involved require further investigations.