Molecular Mechanism of Genistein (Isoflavone) in Prostate Cancer

金雀异黄酮（异黄酮）在前列腺癌中的分子机制

基本信息

批准号：
7458964
负责人：
FAZLUL H. SARKAR
金额：
$ 26.83万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-07-12 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7458964
关键词：
Ablation Adverse effects Age-Years Androgen Receptor Androgens Animal Model Animals Apoptotic Appendix Behavior Binding CWR22Rv1 Cancer Etiology Cancer Patient Cell Death Cell Line Cell Nucleus Cell Proliferation Cell Survival Cells Cessation of life Chemopreventive Agent Complex Condition Confocal Microscopy Cytosol Data Dependence Development Diagnosis Disease Down-Regulation Drug Formulations Epithelial Cells Experimental Animal Model Funding Gelatinase B Gene Targeting Genes Genistein Growth Heat-Shock Proteins 70 Heat-Shock Proteins 90 Hormones Human Immunoprecipitation In Vitro Induction of Apoptosis Intervention Investigation Isoflavones Knowledge LNCaP Lead Letters MAP Kinase Gene Malignant Neoplasms Malignant neoplasm of prostate Mediating Metastatic Neoplasm to the Bone Modeling Molecular Molecular Mechanisms of Action Mutate Neoplasm Metastasis Nuclear Nuclear Protein Nuclear Proteins Nude Mice Oncogenic PC3 cell line Pathway interactions Patients Phosphorylation Play Polymerase Chain Reaction Post-Translational Regulation Prednisone Prevention Prevention approach Primary Neoplasm Principal Investigator Process Progress Reports Prostate Prostate carcinoma Prostate-Specific Antigen Prostatic Neoplasms Publishing Purpose Receptor Cell Receptor Signaling Regulation Relapse Reporter Genes Reporting Research Personnel Role Role Concepts Saints Signal Pathway Signal Transduction Staging TNFSF11 gene Testing Time Transcriptional Regulation Transfection Treatment Efficacy Treatment outcome Tumor Angiogenesis United States United States National Institutes of Health Vascular Endothelial Growth Factors Western Blotting Xenograft Model aging population androgen independent prostate cancer angiogenesis antitumor agent base bone cancer cell cancer therapy cell growth chemotherapeutic agent chemotherapy daidzein design docetaxel gene repression glycitein hormone refractory prostate cancer human disease improved in vivo inhibitor/antagonist insight killings lymph nodes male men mouse model mutant neoplastic cell novel prostate cancer prevention receptor function research study response soy protein isolate steroid hormone trend tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Almost all prostate cancer (PCa) patients who receive androgen ablation therapy will relapse with hormone refractory prostate cancer (HRPC) and eventual bone metastatic disease, for which there is limited or no curative therapy. The majority of HRPC and bone metastatic disease are still androgen receptor (AR) positive but do not respond to therapy due to promiscuous activity of AR together with the activation of Akt/NF-xB signaling among others. Therefore, there is a dire need for the development of novel non-toxic strategies by which AR itself could be inactivated and thereby growth response via AR signaling could be destroyed in order to make an impact in the prevention and treatment of HRPC, which is the main focus of this application. We found that pure genistein as well as soy isoflavone down-regulates AR, PSA, Akt, NF-KB and their target genes (especially MMP-9, uPA, Cox-2 and VEGF which are known to promote invasion and angiogenesis) and induce apoptotic cell death of PCa cell lines but not normal prostate epithelial cells. Moreover, we found that pure genistein increased lymph node metastasis in an orthotopic model of PCa, however such an adverse effect was not observed with soy isoflavone. Based on our progress report and our preliminary results, we hypothesize that soy isoflavone will function as an inhibitor of AR signaling directly or indirectly due to the inactivation of Akt/NF-KB, ultimately causing cell growth inhibition and induction of apoptosis. We further hypothesize that soy isoflavone will inhibit tumor growth in animals and that the exposure of tumors to isoflavone in vivo will result in the down regulation of genes downstream of AR signaling leading to chemo-sensitization to Taxotere (a common chemotherapeutic agent). To test our hypotheses, we designed four specific aims using four relevant PCa cell lines containing wild-type and mutant AR, especially LNCaP derived C4-2B cells that are more akin to HRPC and bone metastasis, to answer the following questions: (a) How is AR down regulated by soy isoflavone and what is the molecular mechanism? (b) What is the cellular consequence of the down regulation of AR? (c) Is this down regulation associated with molecular regulation of NF-KB, RANK, RANKL, MMP-9, uPA, Cox-2 and VEGF and, in turn, results in the inhibition of tumor growth, angiogenesis, invasion and metastasis in an experimental animal model in vivo? (d) Could anti-tumor effects be correlated with inactivation of AR and NF-KB regulated genes, especially MMP-9, uPA, Cox-2 and VEGF in vivo?, and finally (e) Does inactivation of AR cause chemo- sensitization of prostate cancer cells to Taxotere in vitro and in vivo? Understanding of the molecular and cellular mechanism by which isoflavone inactivates AR signaling and, in combination with Taxotere, stops tumor growth in animal models will have a significant impact in the management of patients diagnosed with HRPC and bone metastasis for which there is no curative therapy.

描述（由申请人提供）：接受雄激素消融疗法的几乎所有前列腺癌（PCA）患者将使用激素难治性前列腺癌（HRPC）和最终的骨转移性疾病复发，而治疗疗法有限或没有治疗疗法。大多数HRPC和骨转移性疾病仍然是雄激素受体（AR）阳性，但由于AR的滥交活动以及AKT/NF-XB信号传导的激活而对治疗没有反应。因此，迫切需要开发新型的无毒策略，通过这种策略可以使AR本身被灭活，从而通过AR信号传导来破坏增长反应，以便对HRPC的预防和治疗产生影响，这是本应用的主要重点。我们发现，纯染料木黄酮和大豆异黄酮下调AR，PSA，AKT，NF-KB及其靶基因（尤其是MMP-9，UPA，COX-2和VEGF），已知旨在促进浸润和血管生成），并诱导PCA细胞线的凋亡细胞死亡，但并非正常的前列腺上皮细胞。此外，我们发现在PCA的原位模型中，纯染料木黄酮增加了淋巴结转移，但是与大豆异黄酮未观察到这种不良反应。根据我们的进度报告和初步结果，我们假设大豆异黄酮将由于AKT/NF-KB的失活而直接或间接地作为AR信号传导的抑制剂，最终导致细胞生长抑制和诱导凋亡。我们进一步假设，大豆异黄酮会抑制动物的肿瘤生长，并且在体内暴露于体内异黄酮会导致AR信号下游基因的下降调节，从而导致化学敏化对cantaotere（一种常见的化学治疗剂）。为了检验我们的假设，我们使用四个含有野生型和突变体AR的相关PCA细胞系设计了四个特定目标，尤其是LNCAP衍生的C4-2B细胞，这些C4-2B细胞更像HRPC和骨转移，回答以下问题：（a）如何对AR调节soy isoflavone以及什么是分子机构？（b）AR下调调节的细胞后果是什么？（c）与NF-KB，RANK，RANKL，MMP-9，UPA，COX-2和VEGF的分子调节相关的下调调节是否相关，进而导致抑制Vivo中实验性动物模型中肿瘤生长，血管生成，侵袭，侵袭和转移？（d）抗肿瘤效应是否与AR和NF-KB调控基因的失活相关，尤其是MMP-9，UPA，COX-2和VEGF？在体内？最后（E）AR失活是否会导致对前列腺癌细胞的化学敏感性，以使前列腺癌细胞纳入VACTERE INTIPRO IN VITRO和INVIVO？了解分子和细胞机制通过这种分子和细胞机制使AR信号失活，并与税滴虫结合使用，在动物模型中停止肿瘤的生长将对诊断患有HRPC和骨转移的患者的治疗产生重大影响，没有治疗治疗。