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Human 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.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2006 Feb 15; Vol. 12 (4), pp. 1355-64. - Publication Year :
- 2006
-
Abstract
- 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.<br />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.<br />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.<br />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.
- Subjects :
- Antineoplastic Agents pharmacology
Apoptosis Regulatory Proteins metabolism
Blotting, Western
Caspase 3
Caspases metabolism
Cell Line, Tumor
Cell Membrane Permeability drug effects
Cell Survival drug effects
Dose-Response Relationship, Drug
Enzyme Activation drug effects
Fas Ligand Protein
Flow Cytometry
Histone Deacetylase Inhibitors
Humans
Hydroxamic Acids pharmacology
Melanoma metabolism
Melanoma pathology
Membrane Potentials drug effects
Mitochondrial Membranes drug effects
Mitochondrial Membranes physiology
Necrosis chemically induced
Poly(ADP-ribose) Polymerases
Propidium pharmacokinetics
TNF-Related Apoptosis-Inducing Ligand
Time Factors
Tumor Necrosis Factors pharmacology
Tumor Suppressor Protein p53 metabolism
Vincristine pharmacology
Apoptosis drug effects
Apoptosis Regulatory Proteins pharmacology
Cisplatin pharmacology
Drug Resistance, Neoplasm
Membrane Glycoproteins pharmacology
Tumor Necrosis Factor-alpha pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1078-0432
- Volume :
- 12
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 16489094
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-05-2084