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

Vallo,Stefan; Stege,Henner; Berg,Maximilian; Michaelis,Martin; Winkelmann,Ria; Rothweiler,Florian; Cinatl,Jindrich

doi:10.3892/or.2020.7487

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

Authors:
- Stefan Vallo
- Henner Stege
- Maximilian Berg
- Martin Michaelis
- Ria Winkelmann
- Florian Rothweiler
- Jindrich Cinatl
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Affiliations: Institute of Medical Virology, University Hospital Frankfurt, D‑60596 Frankfurt am Main, Germany, Centre for Molecular Processing and School of Biosciences, University of Kent, CT2 7NZ Canterbury, UK, Dr. Senckenberg Institute of Pathology, University Hospital Frankfurt, D‑60596 Frankfurt am Main, Germany
Published online on: February 3, 2020 https://doi.org/10.3892/or.2020.7487
Pages: 1331-1337

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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.

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