Effects of cisplatin on matrix metalloproteinase-2 in transformed thyroid cells

We investigated the effects of cisplatin (cisPt) on matrix metalloproteinase-2 (MMP-2) gelatinolitic activity in transformed PC E1Araf rat thyroid cells. Cells incubated with increasing cisPt concentrations showed dose- and time-dependent decrease of the MMP-2 protein and activity. CisPt provoked the translocation from the cytosol to the plasma membrane of atypical protein kinase C-zeta (PKC-ζ) and the activation of PKB/AKT. The effect of cisPt on MMP-2 was dependent on PKC-ζ activation since it was potentiated by a myristoylated PKC-ζ pseudo substrate peptide or by PKC-ζ down-regulation by siRNA. Moreover, MMP-2 activity modulation by cisPt was also dependent on PKB/AKT activation since it was decreased by PKB/AKT down-regulation by siRNA or by pharmacological inhibition of PI3K, thus indicating the importance of the balance of PKB/AKT and PKC-ζ in regulating the cisPt effect on MMP-2 activity. The PC E1Araf cells displayed a migratory capacity that was blocked by MMP-2 down-regulation using siRNA or pharmacological inhibition. The inhibition of cell migration was also obtained with cisPt; in cisPt-treated cells the administration of MMP-2 active protein was able to restore cell migration capacity. In conclusion, the decrease of MMP-2 secretion after cisPt was allowed by PKB/AKT and counteracted by PKC-ζ; the cisPt-provoked inhibition of MMP-2 secretion ended in reduction of cell migration.

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