Protease nexin 1 (PN-1; also known as serpine2, GDN, glia-derived nexin precursor, PI7, protease inhibitor 7, PN1, glial-derived neurite promoting factor, PNI, glial-derived nexin 1, nexin, plasminogen activator inhibitor type 1 member 2, serine (or cysteine) proteinase inhibitor clade E member 2, and serpin peptidase inhibitor clade E member 2) is a secreted 43 kDa protein belonging to the serine protease inhibitors family called serpin. PN-1 can inhibit activity of a broad range of enzymes, such as tissue plasminogen activator (tPA), Urokinase-type plasminogen activator (uPA), thrombin, factor XIa, prostasin.
PN-1 has been originally shown to be involved in development, nerve regeneration and function of NMDA receptor through its inhibitory activity.
In the field of cancer, the role of plasminogen activator inhibitor-1 (PAI-1; also known as serpine1), the other major serine protease inhibitor, has been extensively investigated during the past twenty years. Recently, a few studies recently suggested the importance of PN-1 in cancer. PN-1 has been shown to be overexpressed in malignant breast cancer tumours and has been associated with metastasis in oral squamous carcinoma (Candia et al, 2006, Cancer Cell Int., 6:16; Gao et al, 2007, Oral Oncol., April 27, e-publication). It has also been shown that PN-1 is be able to increase local invasion in pancreatic cancer and PN-1 has been one of the genes identified to be associated with tumour genesis generated by adenovirus 12 (Buchholz et al, 2003, Cancer Res., 63(16):4945; Guan et al, 2003, Virology, 309(1):114).
As a conclusion, PN-1 seems to be involved and to be associated with malignancy and invasiveness of cancer cells.
Here, the results of the inventors provide additional evidence going in that direction. Indeed, the inventors show that PN-1 via binding to the low-density lipoprotein receptor-related protein-1 (LRP) receptor, can induce increase in secreted MMP-9 level, a metalloproteinase involved in degradation of extracellular matrix, promoting invasion of cancer cells.
The inventors also showed that knock-down of PN-1 in a very metastatic cell line leads to a decrease of matrix metalloproteinase-9 (MMP-9) expression as well as a decrease of metastatic properties of the cells, as shown by in vivo cancer cells injection experiments in the mouse mammary fat pad. These results lead the inventors to consider PN-1 as a pro-invasive and a pro-metastatic agent and a potential target for cancer therapy.