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Matrix metalloproteinase-9 is upregulated in nucleophosmin-anaplastic lymphoma kinase-positive anaplastic lymphomas and activated at the cell surface by the chaperone heat shock protein 90 to promote cell invasion.
- Source :
-
Cancer research [Cancer Res] 2010 Sep 01; Vol. 70 (17), pp. 6978-87. Date of Electronic Publication: 2010 Aug 10. - Publication Year :
- 2010
-
Abstract
- Many anaplastic large cell lymphomas (ALCL) express the chimeric oncogene NPM-ALK, which drives malignant transformation and invasion. In this study, we show that NPM-ALK expression increases matrix metalloproteinase-9 (MMP-9) expression. Accordingly, we found that 100% of a large panel of ALK(+) ALCL biopsies examined were also MMP-9(+), in contrast to only 36.3% of ALK(-) tumors. Mechanistic studies revealed that Rac1 drove MMP-9 secretion. The MMP inhibitor GM6001 and MMP-9 blocking antibodies abolished the invasiveness of NPM-ALK(+) cells. Interestingly, the hyaluronan receptor CD44 acted as a docking surface for MMP-9 and the chaperone heat shock protein 90 on the cell surface, where MMP-9 was cleaved and activated. Membrane-associated MMP-9 was localized to invadopodia, which display a strong gelatinase activity. Taken together, our observations strengthen the concept that chaperones have a major extracellular role in the regulation of protein activation status, and reveal new factors that are crucial for spreading and invasion of ALK(+) ALCL. They also point out new factors crucial for ALK(+) ALCL.
- Subjects :
- Cell Line, Tumor
Cell Membrane metabolism
Dipeptides pharmacology
Enzyme Activation
Enzyme Precursors metabolism
Humans
Hyaluronan Receptors metabolism
Lymphoma, Large-Cell, Anaplastic genetics
Lymphoma, Large-Cell, Anaplastic pathology
Matrix Metalloproteinase 9 genetics
Matrix Metalloproteinase 9 metabolism
Matrix Metalloproteinase Inhibitors
Neoplasm Invasiveness
Protein-Tyrosine Kinases genetics
Up-Regulation
rac1 GTP-Binding Protein metabolism
HSP90 Heat-Shock Proteins metabolism
Lymphoma, Large-Cell, Anaplastic metabolism
Matrix Metalloproteinase 9 biosynthesis
Protein-Tyrosine Kinases biosynthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 70
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 20699364
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-10-0861