Tissue factor pathway inhibitor 2 is a potent kallikrein-related protease 12 inhibitor

• Published in: Biological chemistry Vol. 402; no. 10; pp. 1257 - 1268
• Main Authors: Lavergne, Marion, Guillon-Munos, Audrey, Lenga Ma Bonda, Woodys, Attucci, Sylvie, Kryza, Thomas, Barascu, Aurélia, Moreau, Thierry, Petit-Courty, Agnès, Sizaret, Damien, Courty, Yves, Iochmann, Sophie, Reverdiau, Pascale
• Format: Journal Article
• Language: English
• Published: Germany De Gruyter 27.09.2021; Walter de Gruyter GmbH
• Subjects: Cancer; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; CCN; Extracellular matrix; Glycoproteins - chemistry; Glycoproteins - metabolism; Humans; Inflammatory diseases; Inhibitors; Kallikrein; Kallikreins - antagonists & inhibitors; Kallikreins - metabolism; Life Sciences; lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lungs; matrix metalloproteinase; Matrix metalloproteinases; Models, Molecular; Plasmin; Protease; protease inhibitor; Proteinase inhibitors; Serine; serine protease; Serine proteinase; Tissue factor; Tissues; Tumors; lung cancer; matrix metalloproteinase; protease inhibitor; serine protease; extracellular matrix; CCN
• ISSN: 1431-6730; 1437-4315; 1437-4315
• DOI: 10.1515/hsz-2020-0389

The protease activities are tightly regulated by inhibitors and dysregulation contribute to pathological processes such as cancer and inflammatory disorders. Tissue factor pathway inhibitor 2 (TFPI-2) is a serine proteases inhibitor, that mainly inhibits plasmin. This protease activated matrix metalloproteases (MMPs) and degraded extracellular matrix. Other serine proteases are implicated in these mechanisms like kallikreins (KLKs). In this study, we identified for the first time that TFPI-2 is a potent inhibitor of KLK5 and 12. Computer modeling showed that the first Kunitz domain of TFPI-2 could interact with residues of KLK12 near the catalytic triad. Furthermore, like plasmin, KLK12 was able to activate proMMP-1 and -3, with no effect on proMMP-9. Thus, the inhibition of KLK12 by TFPI-2 greatly reduced the cascade activation of these MMPs and the cleavage of cysteine-rich 61, a matrix signaling protein. Moreover, when TFPI-2 bound to extracellular matrix, its classical localisation, the KLK12 inhibition was retained. Finally, TFPI-2 was downregulated in human non-small-cell lung tumour tissue as compared with non-affected lung tissue. These data suggest that TFPI-2 is a potent inhibitor of KLK12 and could regulate matrix remodeling and cancer progression mediated by KLK12.