Abstract
Dietary genistein has been linked to lower prostate cancer (PCa) mortality. Metastasis is the ultimate cause of death from PCa. Cell detachment and invasion represent early steps in the metastatic cascade. We had shown that genistein inhibits PCa cell detachment and cell invasion in vitro. Genistein-mediated inhibition of activation of focal adhesion kinase (FAK) and of the p38 mitogen-activated protein kinase (MAPK)-heat shock protein 27 (HSP27) pathway has been shown by us to regulate PCa cell detachment and invasion effects, respectively. To evaluate the antimetastatic potential of genistein, we developed an animal model suited to evaluating antimetastatic drug efficacy. Orthotopically implanted human PC3-M PCa cells formed lung micrometastasis by 4 weeks in >80% of inbred athymic mice. Feeding mice dietary genistein before implantation led to blood concentrations similar to those measured in genistein-consuming men. Genistein decreased metastases by 96%, induced nuclear morphometric changes in PC3-M cells indicative of increased adhesion (i.e., decreased detachment) but did not alter tumor growth. Genistein increased tumor levels of FAK, p38 MAPK, and HSP27 "promotility" proteins. However, the ratio of phosphorylated to total protein trended downward, indicating a failure to increase relative amounts of activated protein. This study describes a murine model of human PCa metastasis well suited for testing antimetastatic drugs. It shows for the first time that dietary concentrations of genistein can inhibit PCa cell metastasis. Increases in promotility proteins support the notion of cellular compensatory responses to antimotility effects induced by therapy. Studies of antimetastatic efficacy in man are warranted and are under way.
Highlights
Prostate cancer (PCa) is the second most common cause of cancer-related death in American men [1]
Our findings suggest that p38 mitogen-activated protein kinase (MAPK) seems to be important
By 4 weeks, metastases to periadrenal lymph nodes and lung had increased to 32% and 84%, respectively
Summary
Prostate cancer (PCa) is the second most common cause of cancer-related death in American men [1]. Death is caused by the formation of PCa metastases [2]. Therapy that could prevent the formation of metastases would have the potential for high. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). V. Ananthanarayanan is currently with the Department of Pathology, University of Illinois, Chicago, Illinois. Olson 8321, 710 North Fairbanks, Chicago, IL 60611-3008. Phone: 312-908-5284; Fax: 312-503-4744; E-mail: r-bergan@ northwestern.edu
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