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Carcinogenesis Advance Access published online on March 31, 2005
Carcinogenesis, doi:10.1093/carcin/bgi081
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oupjournals.org
Received January 12, 2005
Revised March 3, 2005
Accepted March 22, 2005

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

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

Bo Yeon Kim 1, Kyoung A. Kim 1, Osong Kwon 1, Sun Ok Kim 1, Min Soo Kim 1, Beom Seok Kim 1, Won Keun Oh 1, Kun 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 Dept. of Microbiology, College of Natural Sciences, 599-1, Pukyong National University, Daeyeon3-Dong, Nam-Gu, Pusan 608-737, Korea
3 Department of Radiation Medicine, Georgetown University School of Medicine, Washington, District of Columbia 20057-1482, USA

* To whom correspondence should be addressed.
Jong Seog Ahn, E-mail: jsahn{at}kribb.re.kr


  Abstract

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 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 upon IR exposure, 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 proteins caspase-8 and caspase-3, with the level of anti-apoptotic protein Bcl-2 being unaffected, suggesting the involvement of 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.

Keywords: NF-{kappa}B; Ki-Ras; Radiation; Proteosome.
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