Mitogenic effect of urokinase on malignant and unaffected adjacent human renal cells

Abstract

Primary cultures of renal cell carcinomas and of the corresponding normal adjacent kidney tissue from 6 patients were analyzed for the effects of exogenously added urokinase-type plasminogen activator on cell proliferation as compared to the effects of tissue type plasminogen activator, plasmin and dihydrocortisone. Cell proliferation was studied over a period of up to 5 days by measuring 3H-thymidine incorporation as well as cell viability and cell count; conditioned media of the cultures were also analyzed for their plasminogen activator and plasminogen activator inhibitor content. Addition of urokinase stimulated cell proliferation in a time and dose dependent fashion; after 3 days 3H-thymidine incorporation was significantly increased in malignant renal cells (188.3 +/- 28.7%), while it reached in normal renal cells approximately 130% of the 3H-thymidine incorporation of untreated cultures. Tissue-type plasminogen activator had no effect and plasmin decreased cell proliferation slightly while dihydrocortisone inhibited cell proliferation significantly (34.1 +/- 4.9%) in malignant cells. It is concluded that urokinase-type plasminogen activator itself exhibits a mitogenic effect also on primary cultures of renal cell carcinomas.

Protein C inhibitor is expressed in tubular cells of human kidney.

“…uPA plays an important role in the clinical progression of various types of cancers (31,32). The presence of the uPA inhibitor, PCI, in an environment that is exposed to uPA suggests that PCI may play a protective role in normal kidney tissue, blocking the profibrinolytic and mitogenic activity of uPA (33), while directing uPA activity towards the lumen of the filtration system where proteolysis is required to maintain an unrestricted flow of liquids. The current results have significance for understanding the physiology of the human urinary tract and support the idea that uPA-PCI complexes found in human urine are locally produced in the kidney.…”

“…Any pathological process that alters the fibrinolytic balance could potentially have deleterious effects on the kidney function, as it is known that plasma levels of the zymogen of another target protease of PCI, protein C, are significantly decreased in patients with chronic renal insufficiency and uremia (34,35). In view of data showing that uPA has a direct mitogenic effect on primary cultures of renal cells (33), the role of its regulator, PCI, needs to be evaluated in the progression of renal cancer.…”

Urokinase-type plasminogen activator induces proliferation in breast cancer cells

“…The transfection was performed with a vector:FuGENE ratio of 1:3 (w/v). The cells (5x10 5 ) were seeded in 6-well plates on the day before transfection. The transfection complex was made with 3 μl of FuGENE 6 reagent and 1 μg vector DNA in serum-free medium and incubated for 15 min at RT.…”

“…Furthermore, interaction of uPA to uPAR is important for adhesion, motility and migration of cells (4). It was assumed that uPA can exert cytokine-like activity by increasing the proliferation of human epidermal tumor cells and malignant renal cells (5,6). uPA is subdivided into 3 domains: the N-terminal growth factor-like domain, the kringle domain and the C-terminal protease domain.…”

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

“…Митогенная активность урокиназы наб-людалась на многих типах клеток, в том чис-ле на человеческих эпидермальных клетках, нормальных и злокачественных клетках почки и клетках меланомы [96,97]. недавние иссле-дования показали, что пролиферация раковых клеток человека зависит от взаимодействия комплекса uPa-uPar с интегринами, что ве-дет к активации p38 maPK [98].…”