Adenovirus-mediated mda-7 gene expression radiosensitizes non-small cell lung cancer cells via TP53-independent mechanisms.
We examined the ability of adenoviral-mediated expression of the melanoma differentiation associated gene-7 (Ad-mda-7), to radiosensitize non-small cell lung cancer (NSCLC) cell lines (A549 (wt-TP53/wt-RB1) and H1299 (del-TP53/wt-RB1)), and normal human lung fibroblast (NHLF) lines (CCD-16 and MRC-9). Results of clonogenic assays indicated that Ad-mda7 enhanced the radiosensitivity of the NSCLC cells independent of their TP53 gene status. On the other hand, the NHLF cell lines seemed to be relatively resistant to the cytotoxic effects of Ad-mda7 and were not radiosensitized compared with the NSCLC cells. We further examined the basis for this difference in the ability of Ad-mda7 to radiosensitize NSCLC cells compared with normal cells. Radiation-induced apoptosis was restored in the NSCLC lines, but not in the normal lines. Western blot analysis revealed that Ad-mda7 enhances radiosensitivity independently of any ability to upregulate the expression of Fas or Bax in NSCLC cells. Further analysis indicated that phosphorylated c-Jun expression was increased by Ad-mda7 in both A549 and H1299 cells, but not in CCD-16 cells. These results support the use of gene replacement with Ad-mda7 in combination with radiotherapy for the treatment of NSCLC.
Kawabe
Shinichiro
S
Department of Experimental Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas 77030, USA.
Nishikawa
Takashi
T
Munshi
Anupama
A
Roth
Jack A
JA
Chada
Sunil
S
Meyn
Raymond E
RE
D000256:Adenoviridae / Q000235:genetics*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000532:radiotherapy* / Q000628:therapy*; D003474:Curcumin / Q000494:pharmacology; D004307:Dose-Response Relationship, Radiation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016195:G2 Phase; D018014:Gene Transfer Techniques; D016147:Genes, Tumor Suppressor; D006801:Humans; D007378:Interleukins / Q000235:genetics*; D008175:Lung Neoplasms / Q000532:radiotherapy* / Q000628:therapy*; D008938:Mitosis; D015739:Nocodazole / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011836:Radiation Tolerance; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein; D019014:fas Receptor / Q000378:metabolism; D000099180:Interleukin-24
D000970:Antineoplastic Agents; D003474:Curcumin; D004791:Enzyme Inhibitors; D007378:Interleukins; D015739:Nocodazole; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016755:Proto-Oncogene Proteins c-jun; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; D000099180:Interleukin-24; C494826:BAX protein, human