Journal
CLINICAL & EXPERIMENTAL METASTASIS
Volume 24, Issue 7, Pages 513-520Publisher
SPRINGER
DOI: 10.1007/s10585-007-9088-4
Keywords
ERK1/2 MAPK signalling pathway; matrix metalloproteinase-9; PKC delta; urokinase-type plasminogen activator
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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 PKC delta 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 PKC delta using RNAi led to a marked increase in both uPA and MMP-9 secretion, suggesting a physiological role for PKC delta in controlling protease secretion. The MEK-1 inhibitor PD98059 reverted the characteristic pattern of proteases secretion and phospho-ERK1/2 up-regulation observed in PKC delta overexpressors, suggesting that the PKC delta effect is mediated by the MEK/ERK pathway. Our results suggest a dual role for PKC delta 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.
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