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Carcinogenesis Advance Access originally published online on June 1, 2005
Carcinogenesis 2005 26(11):1929-1933; doi:10.1093/carcin/bgi145
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Carcinogenesis vol.26 no.11 © Oxford University Press 2005; all rights reserved.

Ionomycin downregulates ß-catenin/Tcf signaling in colon cancer cell line

Chi Hoon Park, Eun Ryeong Hahm, Ju Hyung Lee, Kyung Chae Jung, Ho Sung Rhee and Chul Hak Yang *

Division of Chemistry and Molecular Engineering, Seoul National University, Seoul 151-742, Korea

* To whom correspondence should be addressed. Tel: +82 2 878 8545; Fax: +82 2 889 1568; Email: chulyang{at}plaza.snu.ac.kr

Functional activation of ß-catenin/Tcf signaling plays an important role in the early events in colorectal carcinogenesis. We examined the effect of ionomycin against ß-catenin/Tcf signaling in colon cancer cells. Reporter gene assay showed that ionomycin inhibited ß-catenin/Tcf signaling efficiently. In addition, the inhibition of ß-catenin/Tcf signaling by ionomycin in HEK293 cells transiently transfected with a constitutively mutant ß-catenin gene, whose product is not phosphorylated by GSK3ß, indicates that its inhibitory mechanism is related to ß-catenin itself or downstream components. To investigate the precise inhibitory mechanism, we performed immunoprecipitation analysis, western blot and electrophoretic mobility shift assay. As a result, our data reveal that the association of ß-catenin and Tcf-4 is disrupted and the amount of ß-catenin product in the nucleus is decreased by ionomycin in a concentration-dependent manner. Moreover, ionomycin strongly suppressed the binding of the Tcf complexes to its specific DNA-binding sites. The significance of the current work is that ionomycin is a negative regulator of ß-catenin/Tcf signaling in colon cancer cells and its inhibitory mechanism is related to the decreased nuclear ß-catenin products and to the suppressed binding of Tcf complexes to consensus DNA.


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