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Carcinogenesis Advance Access published online on December 23, 2004

Carcinogenesis, doi:10.1093/carcin/bgi003
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Oxford University Press
Received October 26, 2004
Revised November 24, 2004
Accepted December 7, 2004

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

Augmentation of differentiation and gap junction function by kaempferol in partially-differentiated colon cancer cells

Yasushi Nakamura 1*, Chia-Cheng Chang 2, Toshio Mori 3, Kenji Sato 1, Kozo Ohtsuki 1, Brad L. Upham 2, and James E. Trosko 2

1 Department of Food Sciences and Nutritional Health, Kyoto Prefectural University, Shimogamo-Hangi, Sakyo, Kyoto 606-8522, Japan
2 Department of Pediatrics & Human Development, and National Institute of Food Safety & Toxicology Center, Michigan State University, East Lansing, MI 48824-1302, USA
3 RI Center, Nara Medical School, 840 Shijo, Kashihara 634-8521, Japan

* To whom correspondence should be addressed.
Yasushi Nakamura, E-mail: yas{at}kpu.ac.jp


   Abstract

Kaempferol induced differentiation in partially-differentiated colon cancer cells (KNC), which expressed low levels of connexin43 protein and connexin43 mRNA. Differentiation was observed by changes in cell morphology and the activity of alkaline phosphatase. Increased differentiation in kaempferol-treated KNC cells correlated with restoration of gap junctional intercellular communication (GJIC), increased levels of connexin43 protein and the phosphorylation status. Phosphorylation (activation) of Stat3 and Erk was also reduced by kaempferol. An inhibitor of Stat3 phosphorylation also induced morphological changes in KNC cells similar to that of kaempferol-treated cells, suggesting that kaempferol-induced differentiation may be mediated by the inhibition of Stat3 phosphorylation. These effects were not observed in HCT116 cells, which is a poorly-differentiated colon cancer cell line and deficient in the expression of connexin43 mRNA and protein. In conclusion, kaempferol might function as an anti-cancer agent by re-establishment of GJIC through enhancement of the expression and phosphorylation of connexin43 protein in a tumorigenic colon cancer cell line that already expresses connexin43 mRNA via a Stat3-dependent mechanism. In contrast, kaempferol had no effect in a tumorigenic colon cancer cell line that did not express connexin43 mRNA, and was deficient in GJIC.

Keywords: Gap junction; kaempferol; differentiation; colon cancer; Stat3.
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