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,
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,
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,
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