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Biochem Pharmacol. 2014 Dec 15;92(4):530-43. doi: 10.1016/j.bcp.2014.09.026. Epub 2014 Oct 12.

Simvastatin induces NFκB/p65 down-regulation and JNK1/c-Jun/ATF-2 activation, leading to matrix metalloproteinase-9 (MMP-9) but not MMP-2 down-regulation in human leukemia cells.

Author information

1
Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.
2
Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. Electronic address: lschang@mail.nsysu.edu.tw.

Abstract

The aim of the present study was to explore the signaling pathways associated with the effect of simvastatin on matrix metalloproteinase-2 (MMP-2)/MMP-9 expression in human leukemia K562 cells. In sharp contrast to its insignificant effect on MMP-2, simvastatin down-regulated MMP-9 protein expression and mRNA levels in K562 cells. Simvastatin-induced Pin1 down-regulation evoked NFκB/p65 degradation. Meanwhile, simvastatin induced JNK-mediated c-Jun and ATF-2 activation. Over-expression of Pin1 suppressed simvastatin-induced MMP-9 down-regulation. Treatment with SP600125 (a JNK inhibitor) or knock-down of JNK1 reduced MMP-2 expression in simvastatin-treated cells. Simvastatin enhanced the binding of c-Jun/ATF-2 with the MMP-2 promoter. Down-regulation of c-Jun or ATF-2 by siRNA revealed that c-Jun/ATF-2 activation was crucial for MMP-2 expression. Suppression of p65 activation or knock-down of Pin1 by shRNA reduced MMP-2 and MMP-9 expression in K562 cells. Over-expression of constitutively active JNK1 rescued MMP-2 expression in Pin1 shRNA-transfected cells. Simvastatin treatment also suppressed MMP-9 but not MMP-2 expression in human leukemia U937 and KU812 cells. Taken together, our data indicate that simvastatin-induced p65 instability leads to MMP-9 down-regulation in leukemia cells, while simvastatin-induced JNK1/c-Jun/ATF-2 activation maintains the MMP-2 expression underlying p65 down-regulation.

KEYWORDS:

AP-1; Bay11-7082 (PubChem CID:5353431); Farnesyl pyrophosphate (PubChem CID:445713); Geranylgeranyl pyrophosphate (PubChem CID:447277); JNK1; MMP-2/MMP-9; NFκB stability; Pin1; SP600125 (PubChem CID:8515); Simvastatin; Simvastatin (PubChem CID:54454)

PMID:
25316568
DOI:
10.1016/j.bcp.2014.09.026
[Indexed for MEDLINE]

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