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-zeta) and the activation of PKB/AKT. The effect of cisPt on MMP-2 was dependent on PKC-zeta activation since it was potentiated by a myristoylated PKC-zeta pseudo substrate peptide or by PKC-zeta 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-zeta 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-zeta; the cisPt-provoked inhibition of MMP-2 secretion ended in reduction of cell migration.
Urso
L
L
Department of Biological and Environmental Sciences and Technologies (Di.S.Te.B.A.), Università del Salento, Lecce, Italy.
Muscella
A
A
Calabriso
N
N
Vetrugno
C
C
Jiménez
E
E
Montiel
M
M
Marsigliante
S
S
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D002461:Cell Line, Transformed; D002945:Cisplatin / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic; D020868:Gene Silencing; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D034741:RNA, Small Interfering; D051381:Rats; D013961:Thyroid Gland / Q000166:cytology / Q000187:drug effects*
D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat; D002945:Cisplatin