Nitric oxide-mediated apoptosis of K-1735 melanoma cells is associated with downregulation of Bcl-2

Keping Xie, Yunfang Wang, Suyun Huang, Lei Xu, Diane Bielenberg, Thomas Salas, David J. McConkey, Weidong Jiang, Isaiah J. Fidler

Research output: Contribution to journalArticlepeer-review

Abstract

Recent studies have shown that the treatment of nonmetastatic K-1735 murine melanoma cells with cytokines induces the production of nitric oxide (NO) and hence cell death. The purpose of this study was to determine the mechanism of this cytokine-induced NO-mediated apoptosis. Incubation of nonmetastatic K-1735 cells with interleukin-1 alpha (IL-1α) and interferon-gamma (IFN-γ) induced high NO production, Bcl-2 downregulation, and apoptotic cell death. In contrast, incubation of metastatic K-1735 cells with IL-1α and IFN-γ did not induce significant production of NO, downregulation of Bcl-2, or cell death. The exposure to exogenous NO derived from the NO donors, sodium nitroprusside (SNP), or GEA5024 produced a dose-dependent apoptotic cell death in both the metastatic and nonmetastatic K-1735 cells, which was associated with downregulation of Bcl-2 at the mRNA level and, to a lesser extent, at the protein level. Nonmetastatic and metastatic K-1735 cells transfected with the Bcl-2 gene were more resistant to apoptosis mediated by both endogenous and exogenous NO. Subsequent to intravenous injection, the tumor cells transfected with the Bcl-2 gene had an increased survival rate in the lungs of nude mice and produced a higher number of experimental lung metastases. These data suggest that NO-induced apoptosis in K-1735 melanoma cells is associated with downregulation of Bcl-2.

Original languageEnglish (US)
Pages (from-to)771-779
Number of pages9
JournalOncogene
Volume15
Issue number7
DOIs
StatePublished - 1997

Keywords

  • Apoptosis
  • Bcl-2
  • Metastasis
  • Nitric oxide

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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