Protein kinase C delta inhibits the production of proteolytic enzymes in murine mammary cells.
In previous studies we have determined that protein kinase C (PKC) delta, a widely expressed member of the novel PKC serine-threonine kinases, induces in vitro changes associated with the acquisition of a malignant phenotype in NMuMG murine mammary cells. In this study we show that PKCdelta overexpression significantly decreases urokinase-type plasminogen activator (uPA) and matrix metalloproteinase-9 (MMP-9) production, two proteases associated with migratory and invasive capacities. This effect is markedly enhanced by treatment with phorbol 12-myristate 13-acetate (PMA). On the other hand, depletion of PKCdelta using RNAi led to a marked increase in both uPA and MMP-9 secretion, suggesting a physiological role for PKCdelta in controlling protease secretion. The MEK-1 inhibitor PD98059 reverted the characteristic pattern of proteases secretion and phospho-ERK1/2 up-regulation observed in PKCdelta overexpressors, suggesting that the PKCdelta effect is mediated by the MEK/ERK pathway. Our results suggest a dual role for PKCdelta in murine mammary cell cancer progression. While this kinase clearly promotes mitogenesis and favors malignant transformation, it also down-modulates the secretion of proteases probably limiting metastatic dissemination.
Grossoni
Valeria C
VC
Research Area, Institute of Oncology Angel H. Roffo, University of Buenos Aires, Av. San Martín 5481, Buenos Aires C1417DTB, Argentina.
Falbo
Karina B
KB
Mauro
Laura V
LV
Krasnapolski
Martín A
MA
Kazanietz
Marcelo G
MG
Bal De Kier Joffé
Elisa D
ED
Urtreger
Alejandro J
AJ
D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic; D015536:Down-Regulation; D005419:Flavonoids / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D008321:Mammary Glands, Animal / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D010447:Peptide Hydrolases / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000502:physiology*; D014162:Transfection; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
D005419:Flavonoids; D051745:Protein Kinase C-delta; D010447:Peptide Hydrolases; D014568:Urokinase-Type Plasminogen Activator; D020780:Matrix Metalloproteinase 9; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one