Monoclonal antibody 4C5 prevents activation of MMP2 and MMP9 by disrupting their interaction with extracellular HSP90 and inhibits formation of metastatic breast cancer cell deposits.
BACKGROUND
Heat shock protein 90 (HSP90) is a molecular chaperone that is considered a new target for the treatment of cancer. Increasing data reveal an extracellular chaperoning activity for HSP90. Here we investigate the interaction of the secreted isoforms of HSP90 with matrix metalloproteinases (MMP) MMP2 and MMP9. Moreover we examine the role of a monoclonal antibody (mAb) against HSP90, mAb 4C5, regarding these interactions and its value as a potential inhibitor of human breast cancer cell invasion and metastasis.


RESULTS
Our results showed that both HSP90alpha and HSP90beta are secreted by MDAMB453 human breast cancer cells and interact with MMP2 and MMP9. MAb 4C5, while not affecting the secretion of inactive MMPs, inhibits their activation by disrupting their interaction extracellularly with both isoforms of HSP90. The in vivo studies revealed that mAb 4C5 significantly inhibits the metastatic deposit formation of MDAMB453 cells into the lungs of SCID mice.


CONCLUSIONS
Both isoforms of HSP90 are secreted by MDAMB453 cells and interact with MMP2 and MMP9. MAb 4C5 prevents MMP2 and MMP9 activation, by disrupting their interaction with HSP90. Finally mAb 4C5 significantly inhibits the metastatic deposit formation of MDAMB453 cells, by preventing their extravasation and infiltration in the lung tissue and therefore it could be used as a potential therapeutic agent for cancer metastasis.
Stellas
Dimitris
D
Department of Biochemistry, Hellenic Pasteur Institute, 127 Vasilissis Sofias Ave, 11521 Athens, Greece.
El Hamidieh
Avraam
A
Patsavoudi
Evangelia
E
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D002277:Carcinoma / Q000188:drug therapy / Q000276:immunology* / Q000556:secondary; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000556:secondary; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011485:Protein Binding / Q000187:drug effects / Q000276:immunology
D000911:Antibodies, Monoclonal; D018841:HSP90 Heat-Shock Proteins; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9