Plasma kallikrein in breast cancer cells: Interactions with urokinase plasminogen activator system and syndecans.

BACKGROUND: During invasive migration, cancer cells use secreted proteases to remove various extracellular matrix components. The urokinase plasminogen activator (uPA) and its receptor (uPAR), together with kallikreins, perform key functions in this proteolytic network through control of various proteases. Plasma kallikrein (PKa) is an important activator of pro-uPA on the cell surface. OBJECTIVES: To examine the role of plasma kallikrein in malignancy, with a particular focus on breast cancer. METHODS: The MCF-7 (non-metastatic) and MDA-MB-231 (metastatic) breast cancer cell lines were analyzed using immunodetection, PCR, and various enzyme activity and cell dynamics assays. RESULTS: Relative mRNA expression of plasma prekallikrein (PK) was detected in both MCF-7 cells and MDA-MB-231 cells. In addition, in both cell types, PK/PKa was found either on the cell surface or inside cells. In MCF-7 cells, fragments of the PKa active site were found in lysates, whereas in MDA-MB-231 cells, PKa was found most inside lysosomes. PKa colocalized better with syndecan-1 (syn-1) on the surface but with syn-4 in cytoplasm. Both cell lines showed activity of either uPA or PKa, but the small increase in PKa activity after treatment with PKa inhibitor PKSI (or with 4-Cl in MDA-MB-231 cells) suggested regulation of PKa on the cell surface by proteolysis. CONCLUSIONS: Our results suggest that PKa has roles in migration, uPAR cleavage, and pro-uPA activation and can be controlled by proteolysis and endocytosis, and that syndecans may function as receptors for these proteins, suggesting a role in recycling processes.