Matrix metalloproteinase-9 regulates tumor cell invasion through cleavage of protease nexin-1.
Matrix metalloproteinase-9 (MMP-9) expression is known to enhance the invasion and metastasis of tumor cells. In previous work based on a proteomic screen, we identified the serpin protease nexin-1 (PN-1) as a potential target of MMP-9. Here, we show that PN-1 is a substrate for MMP-9 and establish...
| Main Authors: | , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
2010
|
| _version_ | 1826277292268060672 |
|---|---|
| author | Xu, D McKee, C Cao, Y Ding, Y Kessler, B Muschel, R |
| author_facet | Xu, D McKee, C Cao, Y Ding, Y Kessler, B Muschel, R |
| author_sort | Xu, D |
| collection | OXFORD |
| description | Matrix metalloproteinase-9 (MMP-9) expression is known to enhance the invasion and metastasis of tumor cells. In previous work based on a proteomic screen, we identified the serpin protease nexin-1 (PN-1) as a potential target of MMP-9. Here, we show that PN-1 is a substrate for MMP-9 and establish a link between PN-1 degradation by MMP-9 and regulation of invasion. PN-1 levels increased in prostate carcinoma cells after downregulation of MMP-9 and in tissues of MMP-9-deficient mice, consistent with PN-1 degradation by MMP-9. We identified three MMP-9 cleavage sites in PN-1 and showed that mutations in those sites made PN-1 more resistant to MMP-9. Urokinase plasminogen activator (uPA) is inhibited by PN-1. MMP-9 augmented uPA activity in the medium of PC3-ML cells by degrading PN-1. Prostate cancer cells, overexpressing PN-1 or treated with MMP-9 shRNA, had reduced cell invasion in Matrigel. PN-1 siRNA restored uPA activity and the invasive capacity. PN-1 mutated in the serpin inhibitory domain, the reactive center loop, failed to inhibit uPA and to reduce Matrigel invasion. This study shows a novel molecular pathway in which MMP-9 regulates uPA activity and tumor cell invasion through cleavage of PN-1. |
| first_indexed | 2024-03-06T23:26:43Z |
| format | Journal article |
| id | oxford-uuid:6a9c11d4-6edf-4083-8f6c-a4b6a1b1f14c |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:26:43Z |
| publishDate | 2010 |
| record_format | dspace |
| spelling | oxford-uuid:6a9c11d4-6edf-4083-8f6c-a4b6a1b1f14c2022-03-26T18:58:37ZMatrix metalloproteinase-9 regulates tumor cell invasion through cleavage of protease nexin-1.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:6a9c11d4-6edf-4083-8f6c-a4b6a1b1f14cEnglishSymplectic Elements at Oxford2010Xu, DMcKee, CCao, YDing, YKessler, BMuschel, RMatrix metalloproteinase-9 (MMP-9) expression is known to enhance the invasion and metastasis of tumor cells. In previous work based on a proteomic screen, we identified the serpin protease nexin-1 (PN-1) as a potential target of MMP-9. Here, we show that PN-1 is a substrate for MMP-9 and establish a link between PN-1 degradation by MMP-9 and regulation of invasion. PN-1 levels increased in prostate carcinoma cells after downregulation of MMP-9 and in tissues of MMP-9-deficient mice, consistent with PN-1 degradation by MMP-9. We identified three MMP-9 cleavage sites in PN-1 and showed that mutations in those sites made PN-1 more resistant to MMP-9. Urokinase plasminogen activator (uPA) is inhibited by PN-1. MMP-9 augmented uPA activity in the medium of PC3-ML cells by degrading PN-1. Prostate cancer cells, overexpressing PN-1 or treated with MMP-9 shRNA, had reduced cell invasion in Matrigel. PN-1 siRNA restored uPA activity and the invasive capacity. PN-1 mutated in the serpin inhibitory domain, the reactive center loop, failed to inhibit uPA and to reduce Matrigel invasion. This study shows a novel molecular pathway in which MMP-9 regulates uPA activity and tumor cell invasion through cleavage of PN-1. |
| spellingShingle | Xu, D McKee, C Cao, Y Ding, Y Kessler, B Muschel, R Matrix metalloproteinase-9 regulates tumor cell invasion through cleavage of protease nexin-1. |
| title | Matrix metalloproteinase-9 regulates tumor cell invasion through cleavage of protease nexin-1. |
| title_full | Matrix metalloproteinase-9 regulates tumor cell invasion through cleavage of protease nexin-1. |
| title_fullStr | Matrix metalloproteinase-9 regulates tumor cell invasion through cleavage of protease nexin-1. |
| title_full_unstemmed | Matrix metalloproteinase-9 regulates tumor cell invasion through cleavage of protease nexin-1. |
| title_short | Matrix metalloproteinase-9 regulates tumor cell invasion through cleavage of protease nexin-1. |
| title_sort | matrix metalloproteinase 9 regulates tumor cell invasion through cleavage of protease nexin 1 |
| work_keys_str_mv | AT xud matrixmetalloproteinase9regulatestumorcellinvasionthroughcleavageofproteasenexin1 AT mckeec matrixmetalloproteinase9regulatestumorcellinvasionthroughcleavageofproteasenexin1 AT caoy matrixmetalloproteinase9regulatestumorcellinvasionthroughcleavageofproteasenexin1 AT dingy matrixmetalloproteinase9regulatestumorcellinvasionthroughcleavageofproteasenexin1 AT kesslerb matrixmetalloproteinase9regulatestumorcellinvasionthroughcleavageofproteasenexin1 AT muschelr matrixmetalloproteinase9regulatestumorcellinvasionthroughcleavageofproteasenexin1 |