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Carcinogenesis Advance Access originally published online on March 31, 2005
Carcinogenesis 2005 26(8):1395-1403; doi:10.1093/carcin/bgi081
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Carcinogenesis vol.26 no.8 © Oxford University Press 2005; all rights reserved.

NF-{kappa}B inhibition radiosensitizes Ki-Ras-transformed cells to ionizing radiation

Bo Yeon Kim 1, {dagger}, Kyung A. Kim 1, {dagger}, Osong Kwon 1, Sun Ok Kim 1, Min Soo Kim 1, Beom Seok Kim 1, Won Keun Oh 1, Gun Do Kim 2, Mira Jung 3 and Jong Seog Ahn 1, *

1 Laboratory of Cellular Signaling Modulators, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong, Daejeon, 305-333, Korea, 2 Department of Microbiology, College of Natural Sciences, 599-1, Pukyong National University, Daeyeon3-Dong, Nam-Gu, Pusan 608-737, Korea and 3 Department of Radiation Medicine, Georgetown University School of Medicine, Washington, DC 20057-1482, USA

* To whom correspondence should be addressed. Tel: +82 42 860 4312; Fax: +82 42 860 4595; Email: jsahn{at}kribb.re.kr

Most cancer cells show resistance to ionizing radiation (IR)-induced cell death. Recently, Ki-Ras was reported to be responsible for the increased radioresistance. We report here that inhibition of IR-induced activaton of nuclear transcription factor kappa B (NF-{kappa}B) but not of either Akt or MAPK kinase (MEK), increased the radiosensitization of Ki-Ras transformed human prostate epithelial 267B1/K-ras cells. Proteosome inhibitor-1 (Pro1) reduced NF-{kappa}B activation, and this inhibition was accompanied by increased levels of cytoplasmic I{kappa}B{alpha} and p65/RelA. However, translocation of p50/NF-{kappa}B1 did not occur on exposure to IR, suggesting the cell-specific involvement of p50 in radiation signaling. Clonogenic cell survival and soft agar assays further confirmed the increased radiosensitivity of 267B1/K-ras cells by proteosome inhibition. In addition, proteosome inhibition enhanced the IR-induced degradation of apoptotic protein caspases 8 and 3, with the level of antiapoptotic protein Bcl-2 being unaffected, suggesting the involvement of an apoptotic process in IR-induced cell death of 267B1/K-ras cells. LY294002 and PD98059, specific inhibitors of phosphatidylinositol-3-kinase (PI3K) and MEK, respectively however, did not affect the radiosensitization. All these results suggest an application of blocking NF-{kappa}B activation pathway to the development of anticancer therapeutics in IR-induced radiotherapy of Ki-Ras-transformed cancer cells.


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