Carcinogenesis Advance Access published online on June 14, 2006
Carcinogenesis, doi:10.1093/carcin/bgl094
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1 Department of Pharmacology, Cancer Research Institute, College of Medicine, Chungnam National University, 6 Munhwa-dong, Jung-gu, Daejeon 301-131, Korea
* To whom correspondence should be addressed. 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-
Received February 20, 2006
Revised May 22, 2006
Accepted May 24, 2006
CANCER BIOLOGY
Sustained activation of protein kinase C down-regulates nuclear factor-
Kyeong Ah Park 1,
Hee Sun Byun 1,
Minho Won 1,
Keum-Jin Yang 1,
Sanghee Shin 1,
Longzhen Piao 1,
Jin Man Kim 2,
Wan-Hee Woon 3,
Eunsung Junn 4,
Jongsun Park 1,
Jeong Ho Seok 1,
and
Gang Min Hur 1 *
B signaling by dissociation of IKK-
and Hsp90 complex in human colonic epithelial cells
2 Department of Pathology, Cancer Research Institute, College of Medicine, Chungnam National University, 6 Munhwa-dong, Jung-gu, Daejeon 301-131, Korea
3 Department of Surgery, Cancer Research Institute, College of Medicine, Chungnam National University, 6 Munhwa-dong, Jung-gu, Daejeon 301-131, Korea
4 Department of Neurology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, NJ 08554
Gang Min Hur, E-mail: gmhur{at}cnu.ac.kr
Abstract 
B in various cell types. In addition to NF-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-B activation. PMA selectively causes the degradation of IB kinases (IKKs) including IKK-
and IKK-
and subsequent inhibition of TNF-induced IKK and NF-B activation in human colon cancer cell line HCT-116, but not in other gastro-intestinal 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-, 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- strongly associates with heat shock protein 90 (Hsp90) in HCT-116 cells, and that this interaction was dramatically reduced after following 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-B system in case of colon cancer cells by disrupting the interaction of IKK- with Hsp90 which may represent a novel regulatory mechanism of PKC-dependent cellular differentiation and limiting proliferation of colonic epithelial cells.B; Hsp90.
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