Bid Cleavage and TRAIL Sensitivity in Urothelial Cell Carcinoma of the Bladder

Abstract

Urothelial cell carcinoma of the bladder (UCCB) has a high propensity to recur after resection. Intravesical bacillus calmetteguerin (BCG) therapy significantly reduces recurrence of UCCB, and response to BCG therapy is believed to be mediated by tumor necrosis factor related apoptosis-inducing ligand (TRAIL). TRAIL has clinical potential as a novel intravesical agent for UCCB, since it selectively induces apoptosis in tumor cells, but not in normal cells. Previously we have examined eleven human UCC cell lines and a non transformed cell line (F2P6) and their sensitivity to TRAIL. In current study, signal transduction molecules, regulating both the death-receptor mediated (extrinsic) and mitochondrial (intrinsic) apoptotic pathways were analyzed. We observed activation of caspase 8, 9, 3, Bid, and cleavage of DFF45 (DNA fragmentation factor-45) in the responsive cell lines as evidence for both extrinsic and intrinsic apoptotic signaling. Moreover, the amount of tBid formed from the cleavage of Bid directly correlated with the sensitivity of UCC cells to TRAIL. TRAIL activates both the extrinsic and the intrinsic apoptotic pathways in UCC cells. The observed resistance related to tBid signaling provides a rationale for targeting both the intrinsic and extrinsic pathways with combination therapies. Anti-apoptotic proteins, such as Bcl-2, would be prime targets of inhibition to increase UCC sensitivity to TRAIL or BCG. Citation:Sun B, Chapman DW, Gupta N, Mak A, Xiao Z, et al. Bid Cleavage and TRAIL Sensitivity in Urothelial Cell Carcinoma of the Bladder. J Urol Nephrol. 2018;5(1): 5. J Urol Nephrol 5(1): 5 (2018) Page 02 ISSN: 2380-0585 anti-cancer property of TRAIL on UCC cells, and investigated the signaling pathways involved. Material and Methods