Tumor necrosis factor‑related apoptosis‑inducing ligand as a therapeutic option in urothelial cancer cells with acquired resistance against first‑line chemotherapy

Abstract

Patients with urothelial carcinoma frequently fail to respond to first-line chemotherapy using cisplatin and gemcitabine due to development of resistant tumor cells. The aim of the present study was to investigate whether an alternative treatment with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) that induces tumor cell death via the extrinsic apoptotic pathway may be effective against chemotherapy-resistant urothelial cancer cell lines. The viability of the urothelial cancer cell line RT112 and its chemotherapy-adapted sublines was investigated by MTT assay. The expression of anti-apoptotic proteins was determined by western blotting and the individual roles of cellular inhibitor of apoptosis protein (cIAP)1, cIAP2, x-linked inhibitor of apoptosis protein (XIAP) and induced myeloid leukemia cell differentiation protein (Mcl-1) were investigated by siRNA-mediated depletion. In particular, the bladder cancer sublines that were resistant to gemcitabine and cisplatin were cross-resistant to TRAIL. Resistant cells displayed upregulation of anti-apoptotic molecules compared with the parental cell line. Treatment with the second mitochondrial activator of caspases (SMAC) mimetic LCL-161 that antagonizes cIAP1, cIAP2 and XIAP resensitized chemoresistant cells to TRAIL. The resensitization of tumor cells to TRAIL was confirmed by depletion of antiapoptotic proteins with siRNA. Collectively, the findings of the present study demonstrated that SMAC mimetic LCL-161 increased the sensitivity of the parental cell line RT112 and chemotherapy-resistant sublines to TRAIL, suggesting that inhibiting anti-apoptotic molecules renders TRAIL therapy highly effective for chemotherapy-sensitive and -resistant urothelial cancer cells.

The Association of Death Receptors and TGF-β1 Expression in Urothelial Bladder Cancer and Their Prognostic Significance

“…The TRAIL apoptosis induction system has attracted the attention of researchers since its discovery because of its ability to trigger apoptosis primarily in tumor cells [8,17,20]. Although TRAIL can interact with several different receptors, only DR4 and DR5 contain the intracellular death domain necessary for apoptotic signal transmission after ligand binding to the receptor.…”

“…Loss of FAS expression was found to significantly correlate with worse prognosis in patients with urothelial carcinomas of the bladder, ureter, and renal pelvis [16]. Apparently, proper identification and clarification of the exact apoptotic machinery and pathways in different tumor cell types may ameliorate the design of more efficacious targeted cancer treatments [1,3,17].…”

Inhibitor of apoptosis proteins as therapeutic targets in bladder cancer

“…Combination treatment with TRAIL and the SMAC mimetic LCL-161 resulted in an increased cytotoxicity compared to monotherapies. Whereas enhanced expression of cIAP1/2 and XIAP was noted after TRAIL treatment, presumably as a response to the pro-apoptotic stimulus, a reduced expression was after combination treatment with TRAIL and LCL-161 (41). In a recent study, the SMAC mimetic ASTX660, also known as Tolinapant, was found to induce necroptosis in apoptosisinsensitive BC cells by turning TNF-a into a cytotoxic signal (42).…”

Targeting Apoptosis to Overcome Chemotherapy Resistance

“…DEBIO-1143 treatment reversed carboplatin-resistance of ovarian cancer cells by inducing apoptotic or necroptotic cell deaths (96). Similarly, first line chemotherapy-resistant urothelial cancer cells well responded to TRAIL after SMAC mimetic treatment (97).…”