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

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-kB) but not of either Akt or MAPK kinase (MEK), increased the radiosensitiza-tion of Ki-Ras transformed human prostate epithelial 267B1/K-ras cells. Proteosome inhibitor-1 (Pro1) reduced NF-kB activation, and this inhibition was accompanied by increased levels of cytoplasmic IkBa and p65/RelA. How-ever, translocation of p50/NF-kB1 did not occur on expos-ure 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 degrada-tion 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, spe-cific inhibitors of phosphatidylinositol-3-kinase (PI3K) and MEK, respectively however, did not affect the radiosensi-tization. All these results suggest an application of blocking NF-kB activation pathway to the development of anti-cancer therapeutics in IR-induced radiotherapy of Ki-Ras-transformed cancer cells