Novel mechanisms of SKP2 and AR signaling on the suppression of prostate cancer

SKP2和AR信号传导抑制前列腺癌的新机制

基本信息

批准号：
10012770
负责人：
Zhenbang Chen
金额：
$ 18.62万
依托单位：
MEHARRY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-26 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10012770
关键词：
AKT inhibition Ablation Acetates African American American Androgen Receptor Androgens Binding Binding Sites Bioinformatics Biometry Biostatistics Core Cancer Etiology Cancer Patient Castration Caucasians Cell Communication Cells Cessation of life Combined Modality Therapy Complex Core Facility Data Defect Development Environment Ethnic group Event Failure Feedback Generations Genes Grant Growth Hormonal In Vitro Incidence Literature MAP Kinase Gene Malignant Neoplasms Malignant neoplasm of prostate Mediating Metabolism Metastatic Prostate Cancer Molecular Molecular Profiling Morbidity - disease rate Mus Mutant Strains Mice Neoplasm Metastasis Oncogenes Oncogenic Operative Surgical Procedures PTEN gene Pathology Pathway interactions Patients Phosphorylation Phosphotransferases Play Prostate Prostatic Prostatic Neoplasms Proto-Oncogene Proteins c-akt Radiation Receptor Down-Regulation Receptor Inhibition Receptor Signaling Recurrence Recurrent disease Regimen Regulation Reporting Resistance Resource Sharing Role SKP2 gene Signal Pathway Skp2 Proteins Testing The Vanderbilt-Ingram Cancer Center at the Vanderbilt University Therapeutic Treatment Failure Tumor Suppressor Genes Tumor Suppressor Proteins Ubiquitination Up-Regulation Xenograft procedure abiraterone advanced prostate cancer androgen deprivation therapy animal care anti-cancer cancer health disparity castration resistant prostate cancer chemotherapy experience in vivo insight insulin secretion knock-down men mortality mouse model novel novel therapeutics nuclear factor 1 prevent prostate cancer cell prostate cancer progression prostate carcinogenesis response side effect small molecule inhibitor tumor ubiquitin-protein ligase

项目摘要

SUMMARY Prostate Cancer (PCa) is the second-leading cause of cancer-related deaths in American men. The morbidity and the mortality to PCa are 2.44-fold higher in African American men as compared to Caucasian counterparts. Therapies such as surgery, radiation and androgen-ablation have been developed to control PCa for patients at different stages. However, the relapse of this disease is reported in many cases, particularly in patients at advanced stage-metastasis, and as a result patients eventually died of the recurrent growth of castration resistant prostate cancer (CRPC). Studies demonstrated that various alterations of tumor suppressors and oncogenes contribute to the initiation and progression of PCa as well as the recurrent growth of CRPC. Emerging evidence revealed that CRPC growth is a complicated malignancy with dysregulation of multiple oncogenic pathways. Mechanisms on the oncogenic signaling pathways leading to CRPC are poorly understood, and their aberrant activations are regulated in a context and environment dependent manner. Yet, it is urgent to explore novel drugs and further to develop efficient treatments in order to reduce the incidence and mortality rate of PCa and to eliminate the disparities among ethnic groups. Aberrant elevation of SKP2 and AR are frequently found in advanced PCa and CRPC. We discovered that SKP2 inactivation partially suppresses PCa progression but also leads to aberrant elevation of AR and FOXA1 pathways. We HYPOTHESIZE that AR elevation confers resistance to SKP2 inhibition in prostate cancer cells and a combined inhibition of SKP2 and AR can effectively suppress the CRPC growth. We propose to test this hypothesis by evaluating the molecular profiling of FOXA1/AR regulated by SKP2, the anti-proliferation effects of co-targeting SKP2 and AR in PCa cells in vitro and its efficacy of combined treatment on the suppression of prostate tumors in mice in vivo. The following specific aims are proposed: 1) Define the mechanisms on the regulation of FOXA1/AR pathways by SKP2 in PCa cells; 2) Study the molecular profiling of FOXA1/AR signaling by SKP2 in PCa cells; and 3) Investigate the efficacy of combined targeting of SKP2 and AR inhibition on the suppression of PCa progression in vivo. Results will provide a novel and efficient therapeutic regimen to suppress CRPC growth.

概括前列腺癌（PCA）是美国男性与癌症相关死亡的第二大原因。发病率与高加索同行相比，非裔美国人的PCA死亡率高2.44倍。已经开发了诸如手术，辐射和雄激素燃料之类的疗法来控制患者的PCA 不同的阶段。但是，在许多情况下报告了这种疾病的复发，尤其是在晚期阶段 - 纳斯塔症，结果患者最终死于castration的复发增长抗性前列腺癌（CRPC）。研究表明，肿瘤抑制剂和致癌基因有助于PCA的启动和进展以及CRPC的复发生长。新兴证据表明，CRPC生长是一种复杂的恶性肿瘤，多发性致癌性失调途径。通往CRPC的致癌信号通路上的机制知之甚少，它们异常激活以上下文和环境依赖性方式调节。然而，迫切需要探索新的药物，进一步开发有效的治疗，以降低PCA的发病率和死亡率并消除种族之间的差异。经常发现SKP2和AR的异常升高在高级PCA和CRPC中。我们发现SKP2失活部分抑制了PCA的进展，但还导致AR和FOXA1途径的异常升高。我们假设AR高程表示对前列腺癌细胞中SKP2抑制的抗性以及对SKP2和AR的综合抑制作用可以有效抑制CRPC增长。我们建议通过评估评估该假设 FOXA1/AR由SKP2调节，PCA细胞中共靶向SKP2和AR的抗增殖作用在体外以及联合治疗对体内小鼠抑制前列腺肿瘤的功效。下列提出了具体目的：1）定义SKP2中FOXA1/AR途径调节的机制 PCA细胞； 2）研究SKP2在PCA细胞中的FOXA1/AR信号传导的分子分析； 3）调查 SKP2和AR抑制对体内PCA进展的抑制的联合靶向的功效。结果将提供一种新颖有效的治疗方案，以抑制CRPC的生长。