Adenoviral-mediated mda-7 expression suppresses DNA repair capacity and radiosensitizes non-small-cell lung cancer cells

Takashi Nishikawa, Anupama Munshi, Michael D. Story, Sheikh Ismail, Craig Stevens, Sunil Chada, Raymond E. Meyn

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

The melanoma differentiation-associated gene-7 (mda-7) was identified by virtue of its enhanced expression in human melanoma cells induced into terminal differentiation. Enforced expression of mda-7 in human cancer cell lines of diverse origins results in the suppression of growth and induction of apoptosis. We have shown that adenoviral-mediated mda-7 (Ad-mda7) radiosensitizes non-small-cell lung cancer (NSCLC) cells by enhancing the apoptotic pathway. To identify the mechanism of this radiosensitization, we examined the level of proteins involved in the nonhomologous end-joining (NHEJ) pathway of DNA double-strand break (DSB) repair. Western blot analysis indicated that the expression of NHEJ pathway components Ku70, XRCC4, and DNA ligase IV was downregulated in NSCLC cells - A549 with Ad-mda7 treatment. No such change was observed in normal human CCD16 fibroblasts previously shown not to be radio-sensitized by Ad-mda7. The biological significance of these changes of expression of proteins critical for repair of radiation-induced DSBs was confirmed via the analysis of DSB rejoining kinetics using pulsed field gel electrophoresis and assessment of host cell reactivation capacity following Ad-mda7 treatment. Based on these results, we hypothesize that Ad-mda7 sensitizes NSCLC cells to ionizing radiation by suppressing the activity of NHEJ, a pathway essential for repair of radiation-induced DSBs.

Original languageEnglish (US)
Pages (from-to)7125-7131
Number of pages7
JournalOncogene
Volume23
Issue number42
DOIs
StatePublished - Sep 16 2004

Keywords

  • Adenovirus
  • DNA repair
  • Lung cancer
  • Nonhomologous end-joining
  • Radiation
  • mda-7

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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