This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhang, X. D. Articles by Hersey, P. Search for Related Content PubMed PubMed Citation Articles by Zhang, X. D. Articles by Hersey, P.

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

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

Requests for reprints: Peter Hersey, Immunology and Oncology Unit, Royal Newcastle Hospital, Room 443, David Maddison Clinical Sciences Building, Corner King & Watt Streets, Newcastle, NSW 2300, Australia. Phone: 61-2-49-236828; Fax: 61-2-49236184; E-mail: peter.hersey{at}newcastle.edu.au.

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.

This article has been cited by other articles:

				C. E. Whibley, K. L. McPhail, R. A. Keyzers, M. F. Maritz, V. D. Leaner, M. J. Birrer, M. T. Davies-Coleman, and D. T. Hendricks Reactive oxygen species mediated apoptosis of esophageal cancer cells induced by marine triprenyl toluquinones and toluhydroquinones Mol. Cancer Ther., September 1, 2007; 6(9): 2535 - 2543. [Abstract] [Full Text] [PDF]

				N. M. Mhaidat, Y. Wang, K. A. Kiejda, X. D. Zhang, and P. Hersey Docetaxel-induced apoptosis in melanoma cells is dependent on activation of caspase-2 Mol. Cancer Ther., February 1, 2007; 6(2): 752 - 761. [Abstract] [Full Text] [PDF]