Indomethacin-induced radiosensitization and inhibition of ionizing radiation-induced NF-κB activation in HeLa cells occur via a mechanism involving p38 MAP kinase

Stephanie Markovina, S. Jack Wei, Luis M. Rene, Imran Zoberi, Nobuo Horikoshi, C. Matthew Bradbury, David Gius

Research output: Contribution to journalArticlepeer-review

69 Scopus citations

Abstract

Although ionizing radiation (IR) activates multiple cellular factors that vary depending on dose and tissue specificity, the activation of NF-κB appears to be a well-conserved response in tumor cells exposed to IR. Recently, it also has been demonstrated that nonsteroidal anti-inflammatory agents inhibit tumor necrosis factor and interleukin-1-induced NF-κB activation and act as radiosensitizing agents. These observations reinforce the growing notion that NF-κB may be a protective cellular factor responding to the cytotoxicity of IR and other damaging stimuli. As such, we addressed the idea and mechanism that NF-κB is a downstream target of the nonsteroidal anti-inflammatory agent indomethacin and is involved in the process of radiosensitization. In this study, we report that indomethacin inhibited IR-induced activation of NF-κB and sensitized HeLa cells to IR-induced cytotoxicity at similar concentrations. Pretreatment of HeLa cells with SB 203580, a pyridinyl imidazole compound that specifically inhibits p38 mitogen-activated protein kinase (MAPK), abrogated the ability of indomethacin to inhibit IR-induced activation of NF-κB and diminished the indomethacin radiosensitizing effect. In addition, the transient genetic activation of p38MAPK inhibited IR induction of NF-κB gene expression in the absence of indomethacin. Finally, permanently transfected cell lines genetically unable to activate NF-κB, because of expression of a dominant negative I-κBα gene, demonstrated increased sensitivity to IR-induced cytotoxicity. Taken together, these results suggest that p38 MAPK is a target involved in indomethacin-induced radiosensitization and that NF-κB may be one downstream target in this process.

Original languageEnglish (US)
Pages (from-to)7689-7696
Number of pages8
JournalCancer Research
Volume61
Issue number20
StatePublished - Oct 15 2001

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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