Adenovirus-mediated gene transduction of truncated I kappa B alpha enhances radiosensitivity in human colon cancer cells.

Abstract

Nuclear factor kappa B (NF-kappa B) is a transcription factor that is known to regulate apoptosis when cells are exposed to DNA-damaging agents such as ionizing radiation and cytotoxic drugs. We sought to determine if inhibition of NF-kappa B could enhance radiosensitivity in human colon cancer cells in vitro and in vivo. To inhibit NF-kappa B activation specifically, we constructed a recombinant adenovirus vector expressing a truncated form of the inhibitor protein I kappa B alpha (I kappa B alpha Delta N) that lacks the phosphorylation sites essential for activation of NF-kappa B, and transfected two human colon cancer cell lines (HT29 and HCT15) with this vector. In vitro colony-forming assays revealed that the overexpression of the stable I kappa B alpha by AxI kappa B alpha Delta N infection significantly suppressed cell growth after irradiation in both cell lines as compared to infection with a control vector, AxLacZ. Treatment with AxI kappa B alpha Delta N and irradiation successfully inhibited the growth of HT29 xenografted subcutaneous tumors in nude mice with an 83.8% volume reduction on day 38 as compared to the untreated tumors. Furthermore, it was demonstrated that apoptosis was increased by adenovirus-mediated gene transduction of I kappa B alpha Delta N in vitro and in vivo. These results indicated that inhibition of NF-kappa B could enhance radiosensitivity through an increase in radiation-induced apoptosis. We believe that radio-gene therapy using adenovirus-mediated gene transduction of I kappa B alpha Delta N could be an attractive candidate as a treatment strategy for colorectal cancer.

• Authors: Tomohide Mukogawa, Fumikazu Koyama, Masaaki Tachibana, Atsushi Takayanagi, Nobuyoshi Shimizu, Hisao Fujii, Masato Ueno, Hiroshi Matsumoto, Taku Takeuchi, Yoshiyuki Nakajima
• Journal: Cancer science (Cancer Sci) Vol. 94 Issue 8 Pg. 745-50 (Aug 2003) ISSN: 1347-9032 [Print] England
• PMID: 12901803 (Publication Type: Journal Article)

Chemical References

• I-kappa B Proteins
• NF-kappa B
• NFKBIA protein, human
• Nfkbia protein, mouse
• Recombinant Proteins
• NF-KappaB Inhibitor alpha

Topics

• Adenoviridae (genetics)
• Cell Line
• Cell Survival (radiation effects)
• Colonic Neoplasms (genetics, virology)
• Dose-Response Relationship, Radiation
• Genetic Vectors
• Humans
• I-kappa B Proteins (genetics, metabolism)
• NF-KappaB Inhibitor alpha
• NF-kappa B (antagonists & inhibitors)
• Radiation Tolerance (genetics)
• Recombinant Proteins (metabolism)
• Transfection
• Tumor Cells, Cultured
• X-Rays