Induction and regulation of tumor necrosis factor-related apoptosis-inducing ligand/Apo-2 ligand-mediated apoptosis in renal cell carcinoma

Thomas S. Griffith, Jonathan M. Fialkov, David L. Scott, David Scott, Richard D. Williams, Nathan R. Wall, Dario C. Altieri, Anthony D. Sandler

Research output: Contribution to journalArticle

79 Citations (Scopus)

Abstract

The lack of effective therapy for disseminated renal cell carcinoma (RCC) has stimulated the search for novel treatments including immunotherapeutic strategies. However, poor therapeutic responses and marked toxicity associated with immunological agents has limited their use. The tumor necrosis factor family member tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo-2 ligand induces apoptosis in a variety of tumor cell types, while having little cytotoxic activity against normal cells. In this study the activation and regulation of TRAIL-induced apoptosis and TRAIL receptor expression in human RCC cell lines and pathologic specimens was examined. TRAIL induced caspase-mediated apoptotic death of RCC cells with variable sensitivities among the cell lines tested. Compared with TRAIL-sensitive RCC cell lines (A-498, ACHN, and 769-P), the TRAIL-resistant RCC cell line (786-0) expressed lesser amounts of the death-inducing TRAIL receptors, and greater amounts of survivin, an inhibitor of apoptosis. Incubation of 786-0 with actinomycin D increased the expression of the death-inducing TRAIL receptors and, concomitantly, decreased the intracellular levels of survivin, resulting in TRAIL-induced apoptotic death. The link between survivin and TRAIL regulation was confirmed when an increase in TRAIL resistance was observed after overexpression of survivin in the TRAIL-sensitive, survivin-negative RCC line A-498. These findings, along with our observation that TRAIL receptors are expressed in RCC tumor tissue, suggest that TRAIL may be useful as a therapeutic agent for RCC and that survivin may partially regulate TRAIL-induced cell death.

Original languageEnglish (US)
Pages (from-to)3093-3099
Number of pages7
JournalCancer Research
Volume62
Issue number11
StatePublished - Jun 1 2002
Externally publishedYes

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TNF-Related Apoptosis-Inducing Ligand
Renal Cell Carcinoma
Tumor Necrosis Factor-alpha
TNF-Related Apoptosis-Inducing Ligand Receptors
Apoptosis
Ligands
Cell Line
Dactinomycin
Caspases
Neoplasms
Cell Death
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Griffith, T. S., Fialkov, J. M., Scott, D. L., Scott, D., Williams, R. D., Wall, N. R., ... Sandler, A. D. (2002). Induction and regulation of tumor necrosis factor-related apoptosis-inducing ligand/Apo-2 ligand-mediated apoptosis in renal cell carcinoma. Cancer Research, 62(11), 3093-3099.

Induction and regulation of tumor necrosis factor-related apoptosis-inducing ligand/Apo-2 ligand-mediated apoptosis in renal cell carcinoma. / Griffith, Thomas S.; Fialkov, Jonathan M.; Scott, David L.; Scott, David; Williams, Richard D.; Wall, Nathan R.; Altieri, Dario C.; Sandler, Anthony D.

In: Cancer Research, Vol. 62, No. 11, 01.06.2002, p. 3093-3099.

Research output: Contribution to journalArticle

Griffith, TS, Fialkov, JM, Scott, DL, Scott, D, Williams, RD, Wall, NR, Altieri, DC & Sandler, AD 2002, 'Induction and regulation of tumor necrosis factor-related apoptosis-inducing ligand/Apo-2 ligand-mediated apoptosis in renal cell carcinoma', Cancer Research, vol. 62, no. 11, pp. 3093-3099.
Griffith, Thomas S. ; Fialkov, Jonathan M. ; Scott, David L. ; Scott, David ; Williams, Richard D. ; Wall, Nathan R. ; Altieri, Dario C. ; Sandler, Anthony D. / Induction and regulation of tumor necrosis factor-related apoptosis-inducing ligand/Apo-2 ligand-mediated apoptosis in renal cell carcinoma. In: Cancer Research. 2002 ; Vol. 62, No. 11. pp. 3093-3099.
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