Inactivation of human tumor cell pro-urokinase by granulocyte elastase.
Supernatant obtained from granulocytes stimulated in the presence of cytochalasin B by the chemotactic peptide N-formyl-norleucyl-leucyl-phenylalanyl-norleucyl-tyrosyl- lysine displayed an inhibitory effect on the plasmin-dependent conversion of tumor urokinase-type plasminogen activator proenzyme (pro-uPA) to the active form of uPA. Moreover, the supernatant was also found to inhibit the fibrinolytic activity of human vulva (A431) and breast (MCF7) carcinoma cell lines, which contain large amounts of pro-uPA, by 87% and 96%, respectively. By using eglin C (elastase inhibitor) and a monoclonal antibody to elastase (proteolytic activity blocker of the enzyme), elastase was identified as the key enzyme of the supernatant in these phenomena. Purified elastase converted pro-uPA to an enzymatically inactive molecule composed of two polypeptide chains of Mr = 33,000 and 22,000 linked to each other by a disulfide bond. Elastase-containing granulocytes were identified by immunohistochemistry techniques in the tissues of squamous cell carcinoma and adenocarcinoma of uterus. The cells were found close to the tumor cells and in the stroma surrounding the tumor nests. By immunohistochemical staining, uPA was also found in the tumor cells. Evidently, elastase released by chemotactically activated granulocytes, which are attracted into tumor tissues, may inhibit the conversion of pro-uPA to enzymatically active uPA in the tumor cells.
Kanayama
N
N
Department of Obstetrics and Gynecology, Hamamatsu University School of Medicine.
Terao
T
T
D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D002630:Chemotactic Factors / Q000494:pharmacology; D004789:Enzyme Activation; D005260:Female; D005342:Fibrinolysis / Q000187:drug effects / Q000502:physiology; D006098:Granulocytes / Q000201:enzymology*; D006801:Humans; D009842:Oligopeptides / Q000494:pharmacology; D010196:Pancreatic Elastase / Q000097:blood* / Q000494:pharmacology; D010960:Plasminogen Activators / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000201:enzymology* / Q000473:pathology; D014594:Uterine Neoplasms / Q000201:enzymology* / Q000473:pathology
D002630:Chemotactic Factors; D009842:Oligopeptides; C021642:F-chemotactic peptide; D010960:Plasminogen Activators; D010196:Pancreatic Elastase; D014568:Urokinase-Type Plasminogen Activator