EPLIN as a Molecular Target of Genistein in Preventing Prostate Cancer Metastasis

染料木素是一种主要的膳食异黄酮，其摄入与前列腺癌（PCa）患者的死亡率降低有关，已成为一种有前景的转移抑制剂。尽管如此，染料木素在阻断癌细胞转移级联中的作用机制仍不甚清楚。在本应用中，我们将验证EPLIN的诱导是染料木素抑制PCa细胞获得侵袭性并阻止肿瘤转移的关键机制。我们提出了两个具体目标。在Aim 1中，我们将阐明染料木素在PCa细胞中上调EPLIN和抑制EMT的分子机制。假设染料木素在转录水平诱导EPLIN表达，从而抑制EMT，抑制侵袭性表型。我们将通过抑制蜗牛依赖的EPLIN启动子抑制来确定染料木素是否激活EPLIN启动子。本研究将探讨染料木素对前列腺癌细胞侵袭性的体外影响。本研究旨在阐明染料木素阻断前列腺癌细胞级联转移的新机制。在Aim 2中，我们将在临床前模型中确定染料木素上调EPLIN和预防转移的体内作用。我们的假设是，在动物模型中，给药染料木素可以有效地增加EPLIN的表达并显著降低转移发生率。我们将建立前列腺癌转移的心脏内模型来评估染料木素的体内疗效

DESCRIPTION (provided by applicant): EPLIN as a Molecular Target of Genistein In Preventing Prostate Cancer Metastasis Genistein, a major dietary isoflavone whose consumption is associated with reduced mortality in prostate cancer (PCa) patients, has emerged as a promising inhibitor of 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 crucial 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. We will determine whether genistein activates EPLIN promoter by inhibiting Snail-dependent repression of EPLIN promoter. The in vitro effects of genistein on the 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 models. The hypothesis is that in vivo administration of genistein could effectively increase EPLIN expression and significantly reduce metastatic incidence in animal models. An intracardiac model for PCa metastasis will be used to evaluate the in vivo efficacy of genistein in upregulating EPLIN, inhibiting EMT and reducing metastatic incidence. These studies will provide mechanistic basis and novel biomarkers for clinical investigation of genistein in the prevention of metastasis at early stages, therefore significantly contributing to our efforts of improving survivorship in PCa patients. PUBLIC HEALTH RELEVANCE: EPLIN as a Molecular Target of Genistein In Preventing Prostate Cancer Metastasis Metastasis is the major cause of death from prostate cancer, the most common cancer in men in Western countries. Although several new drugs are currently available for the management of metastatic disease, these therapies can only extend the median survival by approximately 3 months at high cost, which poses a huge burden on patients, their families and the healthcare system. Given the promise of genistein as a safe, efficacious and cost-effective preventive agent that could be implemented before the development of metastasis, it is imperative to understand the molecular mechanism by which genistein inhibits prostate cancer metastasis. Our application will provide mechanistic basis and novel biomarkers for clinical investigation of genistein in the prevention of metastasis at early stages, which could significantly contribute to our efforts of reducing cancer mortality and improving healthcare in the United States and globally.