Journal Article

NF-κB 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 Kim, Jong Wan Kim, Mira Jung, Cheorl Ho Kim, Jong Seog Ahn and Bo Yeon Kim

in Carcinogenesis

Volume 27, issue 11, pages 2258-2268
ISSN: 0143-3334
Published online June 2006 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgl097
NF-κB inhibition increases chemosensitivity to trichostatin A-induced cell death of Ki-Ras-transformed human prostate epithelial cells

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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-κB activation in 267B1/K-ras human prostate epithelial cancer cells. However, both the NF-κB activation and chemoresistance were reduced by pretreatment with proteasome inhibitor-I (ProI), accompanied by accumulations of both IκBα and p65/RelA (but not p50/NF-κB1) 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 IKKβ, IκBα 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-κB 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-κB 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.

Journal Article.  7255 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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