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lüll Adenoviral-mediated mda-7 expression suppresses DNA repair capacity and radiosensitizes non-small-cell lung cancer cells Nishikawa T; Munshi A; Story MD; Ismail S; Stevens C; Chada S; Meyn REOncogene 2004[Sep]; 23 (42): 7125-31The 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 radiosensitized 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.|*Radiation-Sensitizing Agents[MESH]|Adenoviridae/*genetics[MESH]|Carcinoma, Non-Small-Cell Lung[MESH]|Cell Line[MESH]|Cell Line, Tumor[MESH]|DNA Repair/*genetics[MESH]|Genes, Tumor Suppressor[MESH]|Glioma[MESH]|Humans[MESH]|Interleukins/genetics/*metabolism/radiation effects[MESH]|Lung[MESH]|Lung Neoplasms[MESH]|Radiation, Ionizing[MESH]|Recombinant Proteins/metabolism/radiation effects[MESH]|Transfection[MESH] |