Received for publication March 2, 2006.
Revised May 26, 2006.
Accepted for publication June 13, 2006.

Genistein inhibits MMP-2 activation and prostate cancer cell invasion by blocking TGF-mediated activation of MAPKAPK2-HSP27 pathway

Abstract

Genistein is a candidate cancer chemopreventive drug being tested in clinical trials. We have shown that genistein blocks prostate cancer (PCa) cell invasion, that p38 MAP kinase regulates activation of matrix metalloproteinase type 2 (MMP-2) and cell invasion, and that genistein prevents transforming growth factor (TGF) from activating p38 MAP kinase. More recently, we identified mitogen activated protein kinase-activated protein kinase 2 (MAPKAPK2) and heat shock protein 27 (HSP27) as down stream regulators of p38 MAP kinase. However, MAPKAPK2 and HSP27 can be regulated by factors other than p38 MAP kinase, and HSP27 is up regulated during PCa progression. The current study was undertaken to examine the role of MAPKAPK2 and HSP27 in modulating genistein-mediated regulation of PCa cell invasion. Genistein inhibited TGF-mediated phosphorylation of MAPKAPK2 and HSP27. Inhibitory effects by genistein upon cell signaling, inhibition of MMP-2, and inhibition of invasion were retained when of PC3 and PC3-M cells were transfected with either wild type MAPKAPK2 or HSP27. However, transfection with dominant negative MAPKAPK2 or non-phosphorylateable mutant HSP27 led to decreases in cell invasion, and abrogation of responsiveness to either TGF-mediated increases or genistein-mediated decreases in MMP-2 or invasion. Importantly, after transfection with constitutive active MAPKAPK2 or with pseudophosphorylated HSP27, levels of MMP-2 activation and cell invasion were high and overcame any inhibitory effect of genistein. These findings demonstrate that genistein-mediated inhibition of cell invasion rests upon blocking activation of the MAPKAPK2-HSP27 pathway, and that its activation during cancer progression has the potential to mitigate therapeutic efficacy.

Key words: P38 MAP Kinase, Metastasis

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