RT Journal Article SR Electronic T1 Genistein Induces Phenotypic Reversion of Endoglin Deficiency in Human Prostate Cancer Cells JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 235 OP 242 DO 10.1124/mol.107.038935 VO 73 IS 1 A1 Clarissa S. Craft A1 Li Xu A1 Diana Romero A1 Calvin P. H. Vary A1 Raymond C. Bergan YR 2008 UL http://molpharm.aspetjournals.org/content/73/1/235.abstract AB Genistein has been shown to inhibit human prostate cancer (PCa) cell motility. Endoglin has been identified as an important suppressor of PCa cell motility, and its expression is lost during PCa progression. It is therefore important to determine whether endoglin loss affects genistein's efficacy and, if so, by what mechanism. In the current study, genistein was shown to induce reversion of endoglin-deficient cells to a low motility, endoglin-replete phenotype. Because endoglin suppresses PCa cell motility in an activin-like kinase receptor-2 (ALK2)- and Smad1-dependent manner, we sought to determine whether genistein was activating the ALK2-Smad1 pathway. Although treatment with genistein or overexpression of Smad1 or ALK2 all increased Smad1-responsive promoter activity and decreased cell motility, genistein's efficacy was abrogated by either Smad1 or ALK2 knockdown. Furthermore, transfection of cells with a kinase dead mutant of ALK2 abrogated genistein's efficacy. Together, these findings demonstrate that genistein therapeutically induces reversion to a low-motility phenotype in aggressive endoglin-deficient PCa cells. It does so by activating ALK2-Smad1 endoglin-associated signaling. These findings support the notion that individuals with low endoglin-expressing PCa will benefit from genistein treatment. The American Society for Pharmacology and Experimental Therapeutics