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Carcinogenesis Advance Access originally published online on June 14, 2006
Carcinogenesis 2007 28(1):71-80; doi:10.1093/carcin/bgl094
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Sustained activation of protein kinase C downregulates nuclear factor-{kappa}B signaling by dissociation of IKK-{gamma} and Hsp90 complex in human colonic epithelial cells

Kyeong Ah Park, Hee Sun Byun, Minho Won, Keum-Jin Yang, Sanghee Shin, Longzhen Piao, Jin Man Kim1, Wan-Hee Yoon2, Eunsung Junn3, Jongsun Park, Jeong Ho Seok and Gang Min Hur*

Department of Pharmacology, Cancer Research Institute, College of Medicine, Chungnam National University 6 Munhwa-dong, Jung-gu, Daejeon 301-131, Korea
1 Department of Pathology, Cancer Research Institute, College of Medicine, Chungnam National University 6 Munhwa-dong, Jung-gu, Daejeon 301-131, Korea
2 Department of Surgery, Cancer Research Institute, College of Medicine, Chungnam National University 6 Munhwa-dong, Jung-gu, Daejeon 301-131, Korea
3 Department of Neurology, University of Medicine and Dentistry of New Jersey Robert Wood Johnson Medical School, Piscataway, NJ 08554, USA

*To whom correspondence should be addressed. Email: gmhur{at}cnu.ac.kr

Activation of protein kinase C (PKC) by phorbol 12-myristate 13-acetate (PMA) triggers cellular signals that lead to the activation of the transcription factor NF-{kappa}B (nuclear factor kappaB) in various cell types. In addition to NF-{kappa}B activation by short-time PMA treatment, here we report that the prolonged exposure of human colonic cancer epithelial cells treated with PMA can also lead to a persistent inhibition of NF-{kappa}B activation. PMA selectively causes the degradation of I{kappa}B kinases (IKKs) including IKK-{gamma} and IKK-ß, and subsequent inhibition of tumor necrosis factor (TNF) induced IKK and NF-{kappa}B activation in human colon cancer cell line HCT-116, but not in other gastrointestinal tract cells. The use of Ro-318220 and GO-6983, general PKC inhibitors as well as MG-132, a proteasome-specific inhibitor, abrogated PMA-induced degradation of IKK-{gamma} and recovered the activation of IKK by TNF, suggesting that IKK complex is predominantly degraded by the proteasome pathway in a PKC-dependent manner. We also found that IKK-{gamma} strongly associates with heat shock protein 90 (Hsp90) in HCT-116 cells, and that this interaction was dramatically reduced after exposure to PMA. Furthermore, high levels of Hsp90 expression and enhanced association with IKK were observed in human colon cancer tissues. Taken together, these results suggest that long-term activation of PKC by PMA inhibits NF-{kappa}B system in case of colon cancer cells by disrupting the interaction of IKK-{gamma} with Hsp90, which may represent a novel regulatory mechanism of PKC-dependent cellular differentiation and limited proliferation of colonic epithelial cells.


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K.-J. Yang, S. Shin, L. Piao, E. Shin, Y. Li, K. A. Park, H. S. Byun, M. Won, J. Hong, G. R. Kweon, et al.
Regulation of 3-Phosphoinositide-dependent Protein Kinase-1 (PDK1) by Src Involves Tyrosine Phosphorylation of PDK1 and Src Homology 2 Domain Binding
J. Biol. Chem., January 18, 2008; 283(3): 1480 - 1491.
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