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

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

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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 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.

Original languageEnglish
Pages (from-to)1395-1403
Number of pages9
JournalCarcinogenesis
Volume26
Issue number8
DOIs
Publication statusPublished - 2005 Aug 1
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research

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    Kim, B. Y., Kwon, O., Kim, S. O., Kim, M. S., Kim, B. S., Oh, W. K., Kim, G. D., Jung, M., & Ahn, J. S. (2005). NF-κB inhibition radiosensitizes Ki-Ras-transformed cells to ionizing radiation. Carcinogenesis, 26(8), 1395-1403. https://doi.org/10.1093/carcin/bgi081