Downregulation of c-FLIP promotes caspase-dependent JNK activation and reactive oxygen species accumulation in tumor cells

A. Nakajima, Y. Kojima, M. Nakayama, H. Yagita, K. Okumura, H. Nakano

Research output: Contribution to journalArticlepeer-review

34 Citations (Scopus)

Abstract

Nuclear factor-kappa B (NF-κB) inhibits cell death through suppression of the caspase cascade, the c-Jun N-terminal kinase (JNK) pathway, and reactive oxygen species (ROS) accumulation. To suppress this antiapoptotic function of NF-κB might be a promising strategy to increase susceptibility of tumor cells to stress-induced cell death. We have recently shown that tumor necrosis factor (TNF)α induces caspase-dependent and -independent JNK activation and ROS accumulation in cellular FLICE-inhibitory protein (c-Flip)-/- murine embryonic fibroblasts (MEFs). To apply this observation to tumor therapy, we knocked down c-FLIP by RNA interference in various tumor cells. Consistent with the results using c-Flip-/- MEFs, we found that TNFα stimulation induced caspase-dependent prolonged JNK activation and ROS accumulation, followed by apoptotic and necrotic cell death in various tumor cells. Furthermore, TNFα and Fas induced the cleavage of mitogen-activated protein kinase/ERK kinase kinase (MEKK)1, resulting in generation of a constitutive active form of MEKK1 leading to JNK activation in c-FLIP knockdown cells. Given that ROS accumulation and necrotic cell death enhance inflammation followed by compensatory proliferation of tumor cells, selective suppression of caspase-dependent ROS accumulation will be an alternative strategy to protect cells from ROS-dependent DNA damage and compensatory tumor progression.

Original languageEnglish
Pages (from-to)76-84
Number of pages9
JournalOncogene
Volume27
Issue number1
DOIs
Publication statusPublished - 2008 Jan 3

Keywords

  • Apoptosis
  • Necrosis
  • Reactive oxygen species
  • Tumor necrosis factor
  • c-FLIP
  • c-Jun N-terminal kinase

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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