Genistein inhibits human prostate cancer cell detachment, invasion, and metastasis

Abstract

Prostate cancer (PCa) is the most commonly diagnosed cancer in men in the United States and the second leading cause of cancer death. Death is not caused by the primary tumor but rather by the formation of distinct metastatic tumors. Therefore, prevention of metastasis is of utmost importance. The natural product genistein, found in high amounts in soy products, has been implicated in preventing PCa formation and metastasis in men who consume high amounts of soy. In vitro studies and in vivo rodent models that used human PCa cells, as well as prospective human clinical trials, provide a mechanistic explanation directly supporting genistein as an antimetastatic agent. Specifically, our group showed that genistein inhibits cell detachment, protease production, cell invasion, and human PCa metastasis at concentrations achieved in humans with dietary intake. Finally, phase I and phase II clinical trials conducted by us and others showed that concentrations of genistein associated with antimetastatic efficacy in preclinical models are achievable in humans, and treatment with genistein inhibits pathways that regulate metastatic transformation in human prostate tissue.

FIGURE 1.

Genistein modulates a critical TGF-β signaling pathway in human prostate cancer. A schematic of this signaling network and relevant phenotypes associated with genistein treatment in both mice and men is shown. ALK, activin receptor–like kinase; ENG, endoglin; FAK, focal adhesion kinase; HSP27, heat shock protein 27; MAPKAPK2, mitogen-activated protein kinase–activated protein kinase 2; MEK4, mitogen-activated protein kinase kinase 4; MMP-2, matrix metalloproteinase 2; PCa, prostate cancer; p38 MAP, p38 mitogen-activated protein; RI, TGFb receptor type I ; RII, TGFb receptor type II; TGFβ, transforming growth factor β.

FIGURE 2.

Genistein binds MEK4’s ATP pocket. A homology model of MEK4 [gray; based on a structure of MEK1 as the template (Protein Data Bank entry code: 1s9j)] was constructed by using the Multiple Mapping Method with Multiple Templates (M4T) server interface. To this model, genistein (green) was docked by using Molegro Virtual Docker, and the highest scoring pose was selected. The image was generated by using PyMol (Schroendinger). MEK, mitogen-activated protein kinase kinase.