NF-kappaB inhibition increases chemosensitivity to trichostatin A-induced cell death of Ki-Ras-transformed human prostate epithelial cells.
Chemoresistance has been one of the major problems in anticancer therapy. In our effort to find a potential molecular target for overcoming the chemoresistance in prostate cancer, a promising anticancer drug trichostatin A (TSA) induced cell death was found to be compromised by enhanced NF-kappaB activation in 267B1/K-ras human prostate epithelial cancer cells. However, both the NF-kappaB activation and chemoresistance were reduced by pretreatment with proteasome inhibitor-I (ProI), accompanied by accumulations of both IkappaBalpha and p65/RelA (but not p50/NF-kappaB1) in the cytoplasm. Clonogenic cell survival and soft agar assays further confirmed the increased TSA chemosensitivity of 267B1/K-ras cells by ProI treatment. Moreover, dominant negative mutant of IKKbeta, IkappaBalpha and p65 enhanced the chemosensitization, too. Unexpectedly, using LY294002 and PD98059, phosphatidylinositol-3-kinase and mitogen-activated protein kinase were also implied in TSA chemoresistance through NF-kappaB activation, while these compounds had showed no effect on radiosensitization in the cells. On the other hand, together with TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) assay, activations of caspase-8 and caspase-3 by TSA and ProI were noticed, suggesting the involvement of apoptotic process in chemosensitization of 267B1/K-ras cells. Altogether, these results suggest that blocking the NF-kappaB activation pathway could be an efficient target for improving the TSA chemosensitization and applying to the development of anticancer therapeutics in Ki-Ras-overexpressing tumorigenic cells, including prostate cancer.
Kwon
Osong
O
Laboratory of Cellular Signaling Modulators, Korea Research Institute of Bioscience and Biotechnology (KRIBB) Yuseong, Daejeon, 305-333, Korea.
Kim
Kyong A
KA
Kim
Sun Ok
SO
Ha
Ryong
R
Oh
Won Keun
WK
Kim
Min Soo
MS
Kim
Hee Sik
HS
Kim
Gun Do
GD
Kim
Jong Wan
JW
Jung
Mira
M
Kim
Cheorl Ho
CH
Ahn
Jong Seog
JS
Kim
Bo Yeon
BY
D000818:Animals; D017209:Apoptosis; D002461:Cell Line, Transformed; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D014162:Transfection; D018631:ras Proteins / Q000378:metabolism*
D006877:Hydroxamic Acids; D016328:NF-kappa B; D011500:Protein Synthesis Inhibitors; C012589:trichostatin A; D018631:ras Proteins