Genistein inhibits TGF beta-mediated induction of MMP-2 and cell invasion in human prostate cancer by blocking phosphorylaiton of P38 MAP kinase

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Genistein is being investigated clinically as a potential prostate cancer chemopreventive agent (1). Epidemiological as well as pre-clinical mechanistic studies support the notion of an anti-metastatic mechanism (2). However, Genistein’s ability to modulate cell invasion, a requisite step for metastasis, has not been characterized. It is now shown that Genistein inhibits invasion of PC3 and PC3-M prostate cancer cells, and that it decreases matrix metalloproteinase type 2 (MMP-2) activity. Effects were observed at nanomolar concentrations, thus corresponding to levels attained in the blood with dietary consumption. We have previously shown the importance of p38 MAP kinase in regulating adhesion (3), and of the TGF beta pathway in regulating invasion (4), both in human prostate. We thus went on to show that p38 MAP kinase activity was required for TGF beta-mediated induction of MMP-2, and that genistein inhibited TGF beta-mediated phosphorylation of p38 MAP kinase, as well as TGF beta-mediated increases in cell invasion. Expanding investigations, genistein was shown to inhibit MMP-2 in 6 of 7 prostate cell lines evaluated. Genistein is thus identified as a unique agent which increases prostate cell adhesion, while inhibiting invasion. Such activity, if occurring in vivo, would serve to antagonize metastasis. Activity is mediated, at least in part, by inhibition of TGF beta-mediated induction of p38 MAP kinase phosphorylation. 1. Phase I Pharmacokinetic and Pharmacodynamic Analysis of Unconjugated Soy Isoflavones Administered to Individuals with Cancer. Christopher H. Takimoto, Kira Glover, Xiaoke Huang, Steven A. Hayes, Lilia Gallot, Mary Quinn, Borko D. Jovanovic, Alla Shapiro, Leticia Hernandez, Andrew Goetz, Victor Llorens, Ronald Lieberman, James A. Crowell, Brett A. Poisson, Raymond C. Bergan, Cancer Epidemiology, Biomarkers and Prevention, In Press, 2003. 2. Focal adhesion kinase (FAK) phosphorylation is not required for FAK-β-1-integrin complex formation. Yue-Qin Liu, Edward Kyle, Ronald Lieberman, James Crowell, Gary Kelloff, and Raymond Bergan. Clinical and Experimental Metastasis, 18(3):203-12, 2000. 3. p38 MAP kinase modulates Smad dependent changes in human prostate cell adhesion. Steven A. Hayes, Xiaoke Huang, Suman Kambhampati, Leonidas C. Platanias, and Raymond C. Bergan. Oncogene 22, 4841-4850, 2003. 4. Over expression of endoglin in human prostate cancer suppresses cell detachment, migration and invasion. Yuequin Liu, Borko Jovanovic, Michael Pins, Chung Lee and Raymond C. Bergan. Oncogene, 21(54):8272-8281, 2002.