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Carcinogenesis Advance Access originally published online on June 14, 2006
Carcinogenesis 2006 27(11):2258-2268; doi:10.1093/carcin/bgl097
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

NF-{kappa}B inhibition increases chemosensitivity to trichostatin A-induced cell death of Ki-Ras-transformed human prostate epithelial cells

Osong Kwon, Kyong A Kim, Sun Ok Kim, Ryong Ha, Won Keun Oh, Min Soo Kim, Hee Sik Kim, Gun Do Kim1, Jong Wan Kim2, Mira Jung3, Cheorl Ho Kim4, Jong Seog Ahn and Bo Yeon Kim*

Laboratory of Cellular Signaling Modulators, Korea Research Institute of Bioscience and Biotechnology (KRIBB) Yuseong, Daejeon, 305-333, Korea
1 Department of Microbiology, College of Natural Sciences 599-1, Pukyong National University, Daeyeon3-Dong, Nam-Gu, Pusan 608-737, Korea
2 Department of Radiation, Dangook University School of Medicine Cheonan, Korea
3 Department of Radiation Medicine, Georgetown University School of Medicine Washington, District of Columbia 20057-1482, USA
4 Department of Biological Sciences, Sungkyunkwan University Chunchun-Dong 300, Jangan-Gu, Suwon City, Kyunggi-Do 440-746, Korea

*To whom correspondence should be addressed. Tel: +82 42 860 4297; +82 42 860 4595; Email: bykim{at}kribb.re.kr

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-{kappa}B activation in 267B1/K-ras human prostate epithelial cancer cells. However, both the NF-{kappa}B activation and chemoresistance were reduced by pretreatment with proteasome inhibitor-I (ProI), accompanied by accumulations of both I{kappa}B{alpha} and p65/RelA (but not p50/NF-{kappa}B1) 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 IKKß, I{kappa}B{alpha} 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-{kappa}B 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-{kappa}B 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.


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[Abstract] [Full Text] [PDF]


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