EPLIN as a Molecular Target of Genistein In Preventing Prostate Cancer Metastasis Genistein, a major dietary isoflavone whose consumption is associated with decreased rate of metastasis and reduced risk of mortality in patients, has emerged as a promising inhibitor of PCa metastasis. Nonetheless, the mechanism of action of genistein in blocking metastatic cascade in cancer cells remains largely unknown. In this application, we will test the hypothesis that the induction of EPLIN is a major mechanism wherein genistein inhibits the acquisition of invasiveness by PCa cells and prevents tumor metastasis. We proposed two Specific Aims.
In Aim 1, we will elucidate the molecular mechanism by which genistein upregulates EPLIN and inhibits EMT in PCa cells. The hypothesis is that genistein induces EPLIN expression at transcriptional level, thereby inhibiting EMT and suppressing invasive phenotypes in PCa cells. We will determine whether genistein activates EPLIN promoter by inhibiting Snail-dependent repression of EPLIN promoter. The in vitro effects of genistein on EMT and invasiveness of PCa cells will be examined.
This Aim will elucidate a novel mechanism of action of genistein in blocking the metastatic cascade in PCa cells.
In Aim 2, we will determine the in vivo effects of genistein in upregulating EPLIN and preventing metastasis in pre-clinical PCa models. The hypothesis is that in vivo administration of genistein could effectively increase EPLIN expression and significantly reduce metastatic incidence in animal models. Two experimental models for PCa metastasis, i.e., TRAMP mice and orthotopic inoculation of PCa cells in SCID mice, will be used to evaluate the in vivo efficacy of genistein in upregulating EPLIN, inhibiting EMT and reducing metastatic incidence. These studies will validate EPLIN as a major molecular target of genistein, which could be exploited clinically for preventing PCa metastasis.
EPLIN as a Molecular Target of Genistein In Preventing Prostate Cancer Metastasis Consumption of genistein; a major dietary isoflavone; has been associated with decreased rate of metastasis and reduced risk of mortality in prostate cancer patients. However; the mechanism of action of genistein in blocking the metastatic cascade in cancer cells remains largely unknown. This application will perform in vitro and in vivo studies to elucidate a novel mechanism of action of genistein in inhibiting the acquisition of invasiveness in human prostate cancer cells. The proposed studies will provide mechanistic basis and rationale for clinical investigation of genistein in preventing metastasis at early stages of tumor progression; therefore significantly contributing to our efforts of diverting lethal cancer into a chronic disease.
|Zhang, Shumin; Wang, Yanru; Chen, Zhengjia et al. (2013) Genistein enhances the efficacy of cabazitaxel chemotherapy in metastatic castration-resistant prostate cancer cells. Prostate 73:1681-9|
|Zhang, Shumin; Wang, Xu; Iqbal, Shareen et al. (2013) Epidermal growth factor promotes protein degradation of epithelial protein lost in neoplasm (EPLIN), a putative metastasis suppressor, during epithelial-mesenchymal transition. J Biol Chem 288:1469-79|