Carcinogenesis Advance Access published online on June 14, 2006
Carcinogenesis, doi:10.1093/carcin/bgl097
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1 Laboratory of Cellular Signaling Modulators, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong, Daejeon, 305-333, Korea
* To whom correspondence should be addressed. Chemoresistance has been one of the major problems in anti-cancer therapy. In our effort to find a potential molecular target for overcoming the chemoresistance in prostate cancer, a promising anti-cancer drug trichostatin A (TSA)-induced cell death was found to be compromised by enhanced NF-
Received December 23, 2005
Revised May 12, 2006
Accepted May 19, 2006
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
NF-
Osong Kwon 1,
Kyong A. Kim 1,
Sun Ok Kim 1,
Ryong Ha 1,
Won Keun Oh 1,
Min Soo Kim 1,
Hee Sik Kim 1,
Kun Do Kim 2,
Jong Wan Kim 3,
Mira Jung 4,
Cheorl Ho Kim 5,
Jong Seog Ahn 1,
and
Bo Yeon Kim 1 *
B inhibition increases chemosensitivity to trichostatin A-induced cell death of Ki-Ras-transformed human prostate epithelial cells
2 Department of Microbiology, College of Natural Sciences, 599-1, Pukyong National University, Daeyeon3-Dong, Nam-Gu, Pusan 608-737, Korea
3 Dept. of Radiation, Dangook University School of Medicine, Cheonan, Korea
4 Department of Radiation Medicine, Georgetown University School of Medicine, Washington, District of Columbia 20057-1482, USA
5 Department of Biological Sciences, Sungkyunkwan University, Chunchun-Dong 300, Jangan-Gu, Suwon City, Kyunggi-Do 440-746, Korea
Bo Yeon Kim, E-mail: bykim{at}kribb.re.kr
Abstract 
B activation in 267B1/K-ras human prostate epithelial cancer cells. However, both the NF-B activation and chemoresistance were reduced by pretreatment with proteasome inhibitor-I (ProI), accompanied by accumulations of both IB
and p65/RelA (but not p50/NF-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 IKK
, IB and p65 enhanced the chemosensitization, too. Unexpectedly, using LY294002 and PD98059, phosphatidylinositol-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) were also implied in TSA chemoresistance through NF-B activation, while these compounds had showed no effect on radiosensitization in the cells. On the other hand, together with TUNEL 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-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.B; Ki-Ras; Proteaosome.
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