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.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  G. Zheng, J. G. Lyons, T. K. Tan, Y. Wang, T.-T. Hsu, D. Min, L. Succar, G. K. Rangan, M. Hu, B. R. Henderson, et al. Disruption of E-Cadherin by Matrix Metalloproteinase Directly Mediates Epithelial-Mesenchymal Transition Downstream of Transforming Growth Factor-{beta}1 in Renal Tubular Epithelial Cells Am. J. Pathol., August 1, 2009; 175(2): 580 - 591. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Du, X. Zhang, J. Cardinal, Z. Cao, Z. Guo, L. Shao, and D. A. Geller Wnt/{beta}-Catenin Signaling Regulates Cytokine-Induced Human Inducible Nitric Oxide Synthase Expression by Inhibiting Nuclear Factor-{kappa}B Activation in Cancer Cells Cancer Res., May 1, 2009; 69(9): 3764 - 3771. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Dwivedi, S. C. Slater, and S. J. George MMP-9 and -12 cause N-cadherin shedding and thereby {beta}-catenin signalling and vascular smooth muscle cell proliferation Cardiovasc Res, January 1, 2009; 81(1): 178 - 186. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Ortega, A. Moran, C. de Juan, C. Frias, S. Hernandez, J.-A. Lopez-Asenjo, A. Sanchez-Pernaute, A. Torres, P. Iniesta, and M. Benito Differential Wnt Pathway Gene Expression and E-Cadherin Truncation in Sporadic Colorectal Cancers with and without Microsatellite Instability Clin. Cancer Res., February 15, 2008; 14(4): 995 - 1001. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. You, L. Waeckel, T. G. Ebrahimian, O. Blanc-Brude, P. Foubert, V. Barateau, M. Duriez, S. LeRicousse-Roussanne, J. Vilar, E. Dejana, et al. Increase in Vascular Permeability and Vasodilation Are Critical for Proangiogenic Effects of Stem Cell Therapy Circulation, July 25, 2006; 114(4): 328 - 338. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. I. Fenton and N. G. Hord Stage matters: choosing relevant model systems to address hypotheses in diet and cancer chemoprevention research Carcinogenesis, May 1, 2006; 27(5): 893 - 902. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Dwivedi, G. Pino, A. Banh, Z. Nathu, D. Howchin, P. Margetts, J. G. Sivak, and J. A. West-Mays Matrix Metalloproteinase Inhibitors Suppress Transforming Growth Factor-{beta}-Induced Subcapsular Cataract Formation Am. J. Pathol., January 1, 2006; 168(1): 69 - 79. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. P.Y. Lee, D. D. Mruk, C.-h. Wong, and C. Y. Cheng Regulation of Sertoli-Germ Cell Adherens Junction Dynamics in the Testis Via the Nitric Oxide Synthase (NOS)/cGMP/Protein Kinase G (PRKG)/{beta}-Catenin (CATNB) Signaling Pathway: An In Vitro and In Vivo Study Biol Reprod, September 1, 2005; 73(3): 458 - 471. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Liu, G. L. Borchert, and J. M. Phang Polyoma Enhancer Activator 3, an Ets Transcription Factor, Mediates the Induction of Cyclooxygenase-2 by Nitric Oxide in Colorectal Cancer Cells J. Biol. Chem., April 30, 2004; 279(18): 18694 - 18700. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. B. Uglow, S. Slater, G. B. Sala-Newby, C. M. Aguilera-Garcia, G. D. Angelini, A. C. Newby, and S. J. George Dismantling of Cadherin-Mediated Cell-Cell Contacts Modulates Smooth Muscle Cell Proliferation Circ. Res., June 27, 2003; 92(12): 1314 - 1321. [Abstract] [Full Text] [PDF]
|
|