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.

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.

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.

• Authors: Xu Dong Zhang, Jing Jing Wu, Susan Gillespie, Jodie Borrow, Peter Hersey
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 12 Issue 4 Pg. 1355-64 (Feb 15 2006) ISSN: 1078-0432 [Print] United States
• PMID: 16489094 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Apoptosis Regulatory Proteins
• FASLG protein, human
• Fas Ligand Protein
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• Membrane Glycoproteins
• TNF-Related Apoptosis-Inducing Ligand
• TNFSF10 protein, human
• Tumor Necrosis Factor-alpha
• Tumor Necrosis Factors
• Tumor Suppressor Protein p53
• suberic bishydroxamate
• Propidium
• Vincristine
• Poly(ADP-ribose) Polymerases
• CASP3 protein, human
• Caspase 3
• Caspases
• Cisplatin

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (metabolism, pharmacology)
• Blotting, Western
• Caspase 3
• Caspases (metabolism)
• Cell Line, Tumor
• Cell Membrane Permeability (drug effects)
• Cell Survival (drug effects)
• Cisplatin (pharmacology)
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm
• Enzyme Activation (drug effects)
• Fas Ligand Protein
• Flow Cytometry
• Histone Deacetylase Inhibitors
• Humans
• Hydroxamic Acids (pharmacology)
• Melanoma (metabolism, pathology)
• Membrane Glycoproteins (pharmacology)
• Membrane Potentials (drug effects)
• Mitochondrial Membranes (drug effects, physiology)
• Necrosis (chemically induced)
• Poly(ADP-ribose) Polymerases
• Propidium (pharmacokinetics)
• TNF-Related Apoptosis-Inducing Ligand
• Time Factors
• Tumor Necrosis Factor-alpha (pharmacology)
• Tumor Necrosis Factors (pharmacology)
• Tumor Suppressor Protein p53 (metabolism)
• Vincristine (pharmacology)