Protein kinase Cd inhibits the production of proteolytic enzymes in murine mammary cells

VALERIA C. GROSSONI; KARINA B. FALBO; LAURA V. MAURO; MARTIN A. KRASNAPOLSKI; MARCELO G. KAZANIETZ; ELISA D. BAL DE KIER JOFFÉ; ALEJANDRO J. URTREGER

CLINICAL & EXPERIMENTAL METASTASIS

Springer Netherlands

Lugar: Dordrecht; Año: 2007 vol. 24 p. 513 - 520

0262-0898

In previous studies we have determined that protein kinase C (PKC) d, 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 PKCd 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 PKCd using RNAi led to a marked increase in both uPA and MMP-9 secretion, suggesting a physiological role for PKCd in controlling protease secretion. The MEK-1 inhibitor PD98059 reverted the characteristic pattern of proteases secretion and phospho-ERK1/2 up-regulation observed in PKCd overexpressors, suggesting that the PKCd effect is mediated by the MEK/ERK pathway. Our results suggest a dual role for PKCd 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.