TY - JOUR
T1 - Secretion of urokinase and metalloproteinase-9 induced by staurosporine is dependent on a tyrosine kinase pathway in mammary tumor cells
AU - Aguirre Ghiso, Julio A.
AU - Farías, Eduardo F.
AU - Alonso, Daniel F.
AU - De Kier Joffé, Elisa Bal
PY - 1998
Y1 - 1998
N2 - Urokinase-type plasminogen activator (uPA) is a key serine protease involved in invasion and metastasis. We had shown that overproduction of uPA in tumor cells is controlled by a phospholipase D-protein kinase C-dependent pathway. Now we studied whether other signaling pathways participate in the regulation of constitutive uPA and metalloproteinase (MMP) overproduction in tumor cells. Staurosporine, a protein kinase inhibitor, stimulated uPA and MMP-9 secretion as measured by radial caseinolysis, zymography and Western blotting. Genistein, a specific tyrosine kinase inhibitor, reduced the constitutive and staurosporine-induced uPA and MMP-9 secretion. Interestingly, the phosphatase inhibitor vanadate stimulated uPA secretion. Verapamil, a calcium channel blocker, inhibited both endogenous and PMA- stimulated secretion of uPA but was unable to inhibit staurosporine-induced secretion. The alcohol n-butanol, a phospholipase D and protein kinase C inhibitor, besides inhibiting constitutive uPA secretion, blocked staurosporine-induced secretion. Our results suggest that constitutive and staurosporine-induced uPA and MMP-9 secretion by LM3 murine mammary tumor cells is controlled by an endogenous tyrosine kinase pathway and probably involves protein phosphatases. In addition, the staurosporine-induced signal regulating urokinase secretion is independent of extracellular calcium but dependent on phospholipase D.
AB - Urokinase-type plasminogen activator (uPA) is a key serine protease involved in invasion and metastasis. We had shown that overproduction of uPA in tumor cells is controlled by a phospholipase D-protein kinase C-dependent pathway. Now we studied whether other signaling pathways participate in the regulation of constitutive uPA and metalloproteinase (MMP) overproduction in tumor cells. Staurosporine, a protein kinase inhibitor, stimulated uPA and MMP-9 secretion as measured by radial caseinolysis, zymography and Western blotting. Genistein, a specific tyrosine kinase inhibitor, reduced the constitutive and staurosporine-induced uPA and MMP-9 secretion. Interestingly, the phosphatase inhibitor vanadate stimulated uPA secretion. Verapamil, a calcium channel blocker, inhibited both endogenous and PMA- stimulated secretion of uPA but was unable to inhibit staurosporine-induced secretion. The alcohol n-butanol, a phospholipase D and protein kinase C inhibitor, besides inhibiting constitutive uPA secretion, blocked staurosporine-induced secretion. Our results suggest that constitutive and staurosporine-induced uPA and MMP-9 secretion by LM3 murine mammary tumor cells is controlled by an endogenous tyrosine kinase pathway and probably involves protein phosphatases. In addition, the staurosporine-induced signal regulating urokinase secretion is independent of extracellular calcium but dependent on phospholipase D.
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U2 - 10.1002/(SICI)1097-0215(19980504)76:3<362::AID-IJC13>3.0.CO;2-D
DO - 10.1002/(SICI)1097-0215(19980504)76:3<362::AID-IJC13>3.0.CO;2-D
M3 - Article
C2 - 9579573
AN - SCOPUS:2642680020
SN - 0020-7136
VL - 76
SP - 362
EP - 367
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 3
ER -