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Flowchart: Preparation: Fas        

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Text Box: TrailFas Signaling Pathway                                                      

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Fas ligand and TNF-related apoptosis-inducing ligand induction on infiltrating lymphocytes in bladder carcinoma by bacillus Calmette-Guerin treatment.

Mehmut M, Takeda K, Abe M, Ogata H, Hirose S, Okumura K, Fujime M.

Department of Urology, Juntendo University School of Medicine, Tokyo, Japan.

AIM: To determine the molecular mechanisms underlying the efficacy of bacillus Calmette-Guerin (BCG) therapy against superficial carcinoma of the urinary bladder, we evaluated the expression of cytotoxic molecules on tumor-infiltrating lymphocytes before and after therapy. METHODS: Immunofluorescence staining allowed the specific detection of Fas, Fas ligand (FasL), and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) expression on tumor cells and the respective leukocyte populations in biopsy samples from 6 patients. RESULTS: Significant increases in the infiltration of FasL- and TRAIL-expressing CD4+ T cells and macrophages and FasL-expressing CD8+ T and NK cells were observed after BCG instillation in bladder carcinoma. Moreover, Fas expression was upregulated on tumor cells after BCG instillation. CONCLUSION: The data suggested that the enhanced infiltration of FasL- and/or TRAIL-expressing leukocytes (CD4+ T cells, CD8+ T cells, natural killer cells and macrophages) and the induction of Fas expression on tumor cells may play an important role in the therapeutic effect of BCG instillation. 2005 S. Karger AG, Basel

PMID: 16Human melanoma cells selected for resistance to apoptosis by prolonged exposure to tumor necrosis factor-related apoptosis-inducing ligand are more vulnerable to necrotic cell death induced by Cisplatin.

Zhang XD, Wu JJ, Gillespie S, Borrow J, Hersey P.

Authors' Affiliation: Immunology and Oncology Unit, Royal Newcastle Hospital, Newcastle, Australia.

PURPOSE: Heterogeneous sensitivity of melanoma cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis may lead to outgrowth of TRAIL-resistant cells and limit successful treatment by TRAIL. The present study aims to better understand the biological characteristics of melanoma cells resistant to TRAIL-induced apoptosis.EXPERIMENTAL DESIGN: We generated TRAIL-resistant melanoma cells by prolonged exposure to TRAIL and characterized the cells in terms of their sensitivity to killing induced by a panel of cytotoxic agents using biological and biochemical methods.RESULTS: TRAIL-resistant melanoma cells are cross-resistant to apoptosis induced by another death ligand FasL, the DNA-damaging agent cisplatin, the histone deacetylase inhibitor suberic bishydroxamate, and the antimicrotubule Vinca alkaloid, vincristine. The apoptotic signaling seemed to be inhibited upstream of mitochondrial apoptotic events and was associated with decreased expression of multiple apoptotic mediators, including pro-caspase-8, Fas-associated death domain, Bid, Bim, p53, and the products of its proapoptotic target genes. Despite being resistant to apoptosis, TRAIL-resistant melanoma cells were more vulnerable to cisplatin-induced nonapoptotic cell death. This was characterized by lack of DNA fragmentation, delayed externalization of phosphatidylserine, caspase and p53 independence, and severe mitochondrial disruption, and was preceded by poly(ADP)ribose polymerase (PARP) activation and depletion of intracellular ATP, indicative of necrotic cell death. Inhibition of PARP activity partially converted the mode of cell death from necrosis to apoptosis.CONCLUSIONS: TRAIL-resistant melanoma cells are cross-resistant to apoptosis induced by various apoptotic stimuli but are more sensitive to nonapoptotic cell death induced by cisplatin. Exploration of chemotherapy-induced nonapoptotic cell death may provide an alternative strategy in overcoming resistance of melanoma cells to TRAIL-induced apoptosis.037714 [PubMed - indexed for MEDLINE