NF-kappaB 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-kappaB) 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-kappaB activation, and this inhibition was accompanied by increased levels of cytoplasmic IkappaBalpha and p65/RelA. However, translocation of p50/NF-kappaB1 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-kappaB activation pathway to the development of anticancer therapeutics in IR-induced radiotherapy of Ki-Ras-transformed cancer cells.
Kim
Bo Yeon
BY
Laboratory of Cellular Signaling Modulators, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong, Daejeon, 305-333, Korea. jsahn@kribb.re.kr
Kim
Kyung A
KA
Kwon
Osong
O
Kim
Sun Ok
SO
Kim
Min Soo
MS
Kim
Beom Seok
BS
Oh
Won Keun
WK
Kim
Gun Do
GD
Jung
Mira
M
Ahn
Jong Seog
JS
D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D004307:Dose-Response Relationship, Radiation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects*; D011905:Genes, ras; D006801:Humans; D007700:Kinetics; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000528:radiation effects*; D011471:Prostatic Neoplasms; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology
D002867:Chromones; D004791:Enzyme Inhibitors; D005419:Flavonoids; D009025:Morpholines; D016328:NF-kappa B; D011838:Radiation-Sensitizing Agents; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one