Urokinase-type plasminogen activator induces proliferation in breast cancer cells

Abstract

Abstract. Urokinase-type plasminogen activator (uPA) is implicated in various pathophysiological processes, including extracellular matrix turnover, cell migration and invasion. Our study aimed to determine the role of uPA in both proliferation and mitogen-activated protein kinase (MAPK) pathway. Hence, we analyzed the effects induced by exogeneous addition of domain-specific uPA antibodies and uPAinteracting molecules on proliferation of uPA-suppressed MDA-MB-231 breast cancer cells. uPA expression was reduced to 53% by stable transfection with an antisense/ vector construct and to 65% by siRNA transfection. Immunocytochemical Ki67 staining and flow cytometry (S-phase) analysis indicated a strong decrease of cellular proliferation activity (35% and 38%, respectively). Exogenous addition of high molecular weight-uPA (HMW-uPA) or incubation with the amino terminal fragment (ATF), which lacks the enzymatic activity of uPA, lead to increased cell proliferation. A strong increase of proliferation was absent when the monoclonal antiuPAR antibody IIIF10 (blocking uPA binding site), soluble uPAR (scavenger effect) and phosphatidyl-inositol-specific phopholipase C (PI-PLC, degrading uPAR) was added prior to the addition of HMW-uPA. In conclusion, HMW-uPA and ATF induce proliferation of breast cancer cells by binding to uPAR. Thereby, integrins situated adjacent to uPAR carry the signals into the cell, thus stimulating proliferation that is mediated via the MAPK pathway.

RNA interference-mediated targeting of urokinase plasminogen activator receptor and matrix metalloproteinase-9 gene expression in the IOMM-lee malignant meningioma cell line inhibits tumor growth, tumor cell invasion and angiogenesis

“…Several earlier studies have reported the increased expression of uPAR in various types of cancers (8,14,42) and also its localization and active role at the tumor invasion front (15,43). Furthermore, earlier reports suggested a strong role for uPAR in cell adhesion since uPAR consists of a site for binding to vitronectin (44).…”

“…Furthermore, the uPA-uPAR system brings about several intracellular and intercellular processes including cleavage and activation of plasminogen to plasmin, remodeling of extracellular matrix (ECM), activation of growth factors, and initiation of intracellular signaling in response to various stimuli (7). As such, the uPAuPAR system plays a crucial role in cell adhesion, migration, invasion and cell proliferation, particularly in an altered environment such as cancer (8). Overexpression of uPAR has been reported in various cancers (9)(10)(11).…”

Amplification of the Urokinase-Type Plasminogen Activator Receptor (uPAR) Gene in Ductal Pancreatic Carcinomas Identifies a Clinically High-Risk Group

“…These findings suggest that uPAR gene amplifications render the tumor more sensitive to the prosurvival and antiapoptotic signals of uPA. Recent reports showed that uPAR/uPA-induced proliferation involves activation of ERKs and p38 MAP kinases 11,12 either directly or via release of different growth factors and through dynamic control of cell-matrix interactions. In agreement with previous reports, 24 we found strong uPAR expression in tumor-associated macrophages and fibroblasts of the tumor stroma.…”

“…Integrins situated adjacent to uPAR carry the signals into the cell, thus stimulating proliferation that is mediated via the mitogen-activated protein kinase (MAPK) pathway. 11 The ability of uPA to activate the MAPK pathway by binding to uPAR was reported previously. 6,[12][13][14] There appears to exist a positive feedback loop between uPAR/uPA expression and MAPK: the uPAR/uPA system plays a critical role in maintaining a high level of activated MAPK and at the same time, activated MAP kinases are necessary to maintain uPA and uPAR expression.…”

Role of multidomain structure of urokinase in regulation of growth and remodeling of vessels

“…gyetko и кол-леги показали, что у мышей, нокаутных по урокиназе, пролиферация т-клеток оказалась сниженной [99]. на раковых клетках была по-казана способность ростового домена уроки-назы запускать клеточную пролиферацию на остеобластоподобных клетках [100], клетках меланомы [101], клетках остеосаркомы челове-ка saos-2, раковых клетках молочной желе-зы [102,103]. причем для этого эффекта не-обходимым являлось фукозилирование thr18 в ростовом домене урокиназы [104].…”