Carcinogenesis, Vol. 23, No. 12, 2119-2122,
December 2002
© 2002 Oxford University Press
CARCINOGENESIS |
Matrix metalloproteinase(s) mediate(s) NO-induced dissociation of ß-catenin from membrane bound E-cadherin and formation of nuclear ß-catenin/LEF-1 complex
Metabolism and Cancer Susceptibility Section, Basic Research Laboratory, Center for Cancer Research, NCI-Frederick, MD and
1 Basic Research Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, MD 21702, USA
Modulation of the adenomatous polyposis coli (APC)-ß-catenin pathway by inflammatory mediators and extracellular matrix may be important in colon carcinogenesis. We have recently shown that nitric oxide (NO) induces the accumulation of cytosolic ß-catenin and subsequent formation of the nuclear ß-catenin/lymphocyte enhancing factor (LEF)-1 complex in conditionally immortalized young mouse colonic epithelial (YAMC) cells. In the present study, we explored the mechanism(s) through which NO exerts its effect on cytosolic ß-catenin accumulation and nuclear ß-catenin/LEF-1 complex formation. We found that NO-induced degradation of the membrane bound E-cadherin at tight junctions. Using an anti-E-cadherin antibody specific for its extracellular domain, we detected a 50kDa degradation fragment of E-cadherin (120 kDa) from the culture medium conditioned by YAMC cells exposed to the NO-releasing drug, NOR-1, for 4 and 24 h. As ß-catenin is normally bound to transmembrane E-cadherin and thus anchored to the cytoskeleton structure, the degradation of E-cadherin induced by NO may cause dissociation of ß-catenin from membrane bound E-cadherin. This was demonstrated by the detection of ß-catenin accumulation in the soluble cytosolic fractions in YAMC after exposure to NO-releasing drugs. Furthermore, the degradation of E-cadherin and the release of ß-catenin to cytosol were accompanied by the formation of nuclear ß-catenin/LEF-1 complex, demonstrating the dissociation of ß-catenin from E-cadherin may be responsible for the activation of ß-catenin/LEF-1 transcription complex. Co-treatment with NO donors and broad-spectrum matrix metalloproteinase (MMP) inhibitors TIMP-1 (100 ng/ml), GM6001 (10 µM) and GM1489 (10 µM) abolished the degradation of E-cadherin induced by NO as demonstrated by western blot analysis. These MMP inhibitors also blocked the cytosolic accumulation of ß-catenin and nuclear formation of ß-catenin/LEF-1 complex. The sum effect of MMP inhibitors demonstrated that NO-induced activation of MMP may cause the degradation of E-cadherin and the subsequent dissociation of ß-catenin, thereby contributing to the cytosolic accumulation of ß-catenin and nuclear formation of ß-catenin/LEF-1 complex.
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