Intracellular regulation of TRAIL-induced apoptosis in human melanoma cells

Thomas S. Griffith, Wilson A. Chin, Glenn C. Jackson, David H. Lynch, Marek Z. Kubin

Research output: Contribution to journalArticle

604 Scopus citations

Abstract

The observation that TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF cytokine family, induces apoptosis in a number of different tumor cell types led us to compare the tumoricidal effects of TRAIL to those of other TNF family molecules on human melanoma cells. We found that a high proportion of the melanoma cell lines tested were killed by TRAIL, whereas all the melanoma lines were resistant to the other TNF family cytokines tested. TRAIL-induced death was characterized by caspase activation and cellular protein cleavage within minutes of TRAIL addition, and death could be completely inhibited by the caspase inhibitors Ile-Glu-Thr-Asp (IETD) and Val-Ala-Asp (VAD), indicating the presence of a TRAIL receptor signaling pathway similar to that identified for Fas and TNF receptors. Specific TRAIL receptor expression was determined by RT-PCR, and the presence of mRNA encoding the 'protective' TRAIL receptors did not correspond to resistance or sensitivity to TRAIL-induced apoptosis. Addition of protein synthesis inhibitors to TRAIL-resistant melanomas rendered them sensitive to TRAIL, indicating that the presence or the absence of intracellular apoptosis inhibitors may mediate resistance or sensitivity to TRAIL-mediated apoptosis. Expression of one such inhibitor, FLICE-inhibitory protein (FLIP), was highest in the TRAIL-resistant melanomas, while being low or undetectable in the TRAIL-sensitive melanomas. Furthermore, addition of actinomycin D to TRAIL-resistant melanomas resulted in decreased intracellular concentrations of FLIP, which correlated with their acquisition of TRAIL sensitivity. Collectively, our results indicate that TRAIL-induced apoptosis occurs through a caspase signaling cascade and that resistance is controlled by intracellular regulators of apoptosis.

Original languageEnglish (US)
Pages (from-to)2833-2840
Number of pages8
JournalJournal of Immunology
Volume161
Issue number6
StatePublished - Sep 15 1998

Fingerprint Dive into the research topics of 'Intracellular regulation of TRAIL-induced apoptosis in human melanoma cells'. Together they form a unique fingerprint.

  • Cite this

    Griffith, T. S., Chin, W. A., Jackson, G. C., Lynch, D. H., & Kubin, M. Z. (1998). Intracellular regulation of TRAIL-induced apoptosis in human melanoma cells. Journal of Immunology, 161(6), 2833-2840.