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Genistein is a candidate cancer chemopreventive agent found in soy. We showed that genistein inhibits TGFΒ-mediated activation of p38 mitogen-activated protein kinase (p38 MAP kinase), inhibition of matrix metalloproteinase type 2 (MMP-2), and prostate cancer (PCa) cell invasion. More recently, we demonstrated that mitogen activated protein kinase-activated protein kinase 2 (MAPKAPK2) and heat shock protein 27 (HSP27) also regulate invasion, and are down stream of p38 MAP kinase. However, factors other than p38 MAP kinase can regulate the activity of MAPKAPK2 and HSP27. Importantly, others have shown that HSP27 is up regulated during PCa progression. Studies were therefore performed to test the hypothesis that the MAPKAPK2-HSP27 pathway plays an important role in mediating genisteins’s anti-metastatic activity. Genistein inhibited TGFΒ-mediated phosphorylation of MAPKAPK2 and HSP27, MMP-2 activation and cell invasion, in the presence of wild type MAPKAPK2 and HSP27. When transfected with dominant negative constructs, cell invasion was decreased, and responsiveness to either TGFΒ or genistein was abrogated. When transfected with constitutive active MAPKAPK2 or pseudophosphorylated HSP27, baseline levels of MMP-2 activation and cell invasion were high and overcame any inhibitory effect of genistein. These findings demonstrate that genistein is acting at the level of p38 MAP kinase, but that its anti-invasive effects can be overcome by over activation of the MAPKAPK2-HSP27 pathway.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]