Induction of caspase 8 by interferon γ renders some neuroblastoma (NB) cells sensitive to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) but reveals that a lack of membrane TR1/TR2 also contributes to TRAIL resistance in NB

Xuezhong Yang, Melinda S. Merchant, Maria E. Romero, Maria Tsokos, Leonard H. Wexler, Udo Kontny, Crystal L. Mackall, Carol J. Thiele

Research output: Contribution to journalArticlepeer-review

Abstract

The resistance of neuroblastoma (NB) cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis has been attributed to a lack of caspase 8 expression. Here we demonstrate a clinically applicable molecular targeting strategy that not only increases caspase 8 expression ex vivo in NB cell lines but also in the tumor tissues of NB patients receiving IFN-γ treatment. We identify the functional caspase 8 promoter, which is different from the methylated region reported previously, and show promoter activity is up-regulated by IFN-γ through a IFN-γ activation site-containing region. IFN-γ also induces TRAIL expression in NB cell lines. However, the IFN-γ restoration of caspase 8 in some NB cells revealed persistent TRAIL resistance in most NB cell lines examined. This additional lesion in the TRAIL path is because of a loss of cell membrane TRAIL receptors (TR1/TR2) not only in cell lines but in most of the NB tumor tissues evaluated. Restoration of TR2 expression by transfection enhances IFN-γ-induced TRAIL sensitivity. Furthermore, we have found that we can improve TRAIL sensitivity in NB by reconstituting caspase 8 with IFN-γ and TR2 with chemotherapeutic agents.

Original languageEnglish (US)
Pages (from-to)1122-1129
Number of pages8
JournalCancer Research
Volume63
Issue number5
StatePublished - Mar 1 2003

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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