Journal Article

NF-κB inhibition radiosensitizes Ki-Ras-transformed cells to ionizing radiation

Bo Yeon Kim, Kyung A. Kim, Osong Kwon, Sun Ok Kim, Min Soo Kim, Beom Seok Kim, Won Keun Oh, Gun Do Kim, Mira Jung and Jong Seog Ahn

in Carcinogenesis

Volume 26, issue 8, pages 1395-1403
Published in print August 2005 | ISSN: 0143-3334
Published online March 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi081
NF-κB inhibition radiosensitizes Ki-Ras-transformed cells to ionizing radiation

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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-κB) 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-κB activation, and this inhibition was accompanied by increased levels of cytoplasmic IκBα and p65/RelA. However, translocation of p50/NF-κB1 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-κB activation pathway to the development of anticancer therapeutics in IR-induced radiotherapy of Ki-Ras-transformed cancer cells.

Keywords: DTT, dithiothreitol; EMSA, electromobility shift assay; FT1, farnesyltransferase inhibitor-I; IR, ionizing radiation; MAPK, mitogen-activated protein kinase; NK-κB, nuclear transcription factor kappa B; PI3K, phosphatidylinositol-3-kinase; PMSF, phenylmethylsulfonyl fluoride; Pro1, proteosome inhibitor-1; SS, sulindac sulfide; TNFα, tumor necrosis factor α

Journal Article.  6480 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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