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Journal of Environmental Pathology, Toxicology and Oncology
IF: 1.241 5-Year IF: 1.349 SJR: 0.519 SNIP: 0.613 CiteScore™: 1.61

ISSN Print: 0731-8898
ISSN Online: 2162-6537

Journal of Environmental Pathology, Toxicology and Oncology

DOI: 10.1615/JEnvPathToxOncol.v24.i1.20
pages 3-18

Cell Membrane-Associated MT1-MMP-Dependent Activation of Pro-MMP-2 in A375 Melanoma Cells

Aniruddha Banerji
Department of Receptor Biology and Tumor Metastasis, Chittaranjan National Cancer Institute, 37 S.P. Mukherjee Road, Kolkata-700 026, India
Jayati Chakrabarti
Department of Receptor Biology and Tumor Metastasis, Chittaranjan National Cancer Institute, 37 S.P. Mukherjee Road, Kolkata-700 026, India
Aparna Mitra
Department of Receptor Biology and Tumor Metastasis, Chittaranjan National Cancer Institute, 37 S.P. Mukherjee Road, Kolkata-700 026, India
Amitava Chatterjee
Department of Receptor Biology and Tumor Metastasis, Chittaranjan National Cancer Institute, 37 S.P. Mukherjee Road, Kolkata-700 026, India

ABSTRACT

Matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, can degrade extracellular matrix components under physiological conditions and during cancer invasion and metastasis. Among the MMPs, the 72 kDa type IV collagenase MMP-2 (gelatinase A) is activated in a membrane-associated manner by an activation complex composed of membrane type 1 matrix metalloproteinase (MT1-MMP), tissue inhibitor of matrixmetalloproteinase-2 (TIMP-2), and pro-MMP-2 in the presence of αvβ3 integrin receptor. The activation of pro-MMP-2 correlates with increased occurrence of metastases. Increased MMP-2 activity has been demonstrated in many human tumors. In the present communication, we studied cell surface-associated activation of MMP-2 (72 kDa collagenase type IV) in the moderately metastatic human melanoma cell line A375. Results: Activation of purified 72 kDa collagenase type IV, pro-MMP-2 from cervical cancer tissue homogenate and from serum-free culture medium of HT1080 cells grown in presence of concanavalin A, by A375 cells, was shown by gelatin zymography. A375 cells activated only pro-MMP-2 from purified MMP-9/MMP-2 mixture indicating that the activation is specific for MMP-2. Activation of MMP-2 and purified collagenase type IV by A375 membrane fraction and membrane extract was also demonstrated by gelatin zymography. When A375 cells were first incubated with anti-MT1-MMP polyclonal antibody, activation of collagenase type IV was significantly decreased, indicating that membrane-associated MMP-2 activation is MT1-MMP-mediated. Immunocytochemistry showed MT1-MMP localization at focal adhesion sites. The presence of the components of activation complex—MT1-MMP and integrin αvβ3—were confirmed by Western blot, cell adhesion assay, and integrin subunit assay. Conclusion: Our experimental findings furnish another example of the unique membrane-associated MMP-2 activation mechanism in A375 melanoma cells and clearly indicate the role of MT1-MMP in MMP-2 activation. The information could help in developing new therapies designed to interfere with MMP activation and management of cancer and metastases.


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