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 journalArticle

27 Citations (Scopus)

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

Fingerprint

Non-Small Cell Lung Carcinoma
DNA Repair
Melanoma
Gene Expression
DNA End-Joining Repair
Radiation
Double-Stranded DNA Breaks
Pulsed Field Gel Electrophoresis
Ionizing Radiation
Radio
Genes
Proteins
Down-Regulation
Fibroblasts
Western Blotting
Apoptosis
Cell Line
Growth
Neoplasms
1,2-di-(4-sulfamidophenyl)-4-butylpyrazolidine-3,5-dione

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Adenoviral-mediated mda-7 expression suppresses DNA repair capacity and radiosensitizes non-small-cell lung cancer cells. / Nishikawa, Takashi; Munshi, Anupama; Story, Michael D.; Ismail, Sheikh; Stevens, Craig; Chada, Sunil; Meyn, Raymond E.

In: Oncogene, Vol. 23, No. 42, 16.09.2004, p. 7125-7131.

Research output: Contribution to journalArticle

Nishikawa, Takashi ; Munshi, Anupama ; Story, Michael D. ; Ismail, Sheikh ; Stevens, Craig ; Chada, Sunil ; Meyn, Raymond E. / Adenoviral-mediated mda-7 expression suppresses DNA repair capacity and radiosensitizes non-small-cell lung cancer cells. In: Oncogene. 2004 ; Vol. 23, No. 42. pp. 7125-7131.
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