Effectors of protein kinase C-mediated tumor progression

蛋白激酶 C 介导的肿瘤进展的效应器

基本信息

批准号：
9042748
负责人：
MARCELO G. KAZANIETZ
金额：
$ 38.97万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2020-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9042748
关键词：
Animals Anti-Inflammatory Agents Anti-inflammatory Apoptosis Automobile Driving Breast Cancer Burden Cancer Cell Growth Cancer Patient Castration Cell model Cells Chemoprevention Chemopreventive Agent Collection Colon Carcinoma Coxibs Development Diagnosis Dinoprostone Disease Disease Progression Effectiveness Engineering Enzymes Epidemiology Epithelial Epithelial Cells Gene Deletion Generations Genes Genetically Engineered Mouse Gleason Grade for Prostate Cancer Goals Growth Head and Neck Cancer Human Implant Individual Laboratories Lead Lesion Link Lung Maintenance Malignant Neoplasms Malignant neoplasm of prostate Mediating Modeling Mus Mutation Neoplasm Metastasis Nude Mice Oncogenic Pathology Pathway interactions Patients Pharmaceutical Preparations Phenotype Phosphotransferases Play Prevention Primary Neoplasm Production Prostaglandins Prostate Prostate Adenocarcinoma Prostatectomy Prostatic Intraepithelial Neoplasias Prostatic Neoplasms Protein Isoforms Protein Kinase C Recurrence Research Design Resistance Risk Role Sampling Signal Transduction Specimen Testing Therapeutic Transgenic Mice Transgenic Organisms Tumor Suppressor Proteins Tumorigenicity Up-Regulation WFDC2 gene Xenograft procedure angiogenesis autocrine cyclooxygenase 2 in vivo killings migration mouse PGE synthase 1 mouse model novel overexpression patient subsets personalized medicine prevent prognostic prostanoid receptor EP1 prostate cancer cell protein kinase C epsilon public health relevance receptor response small hairpin RNA targeted treatment therapy development tumor tumor growth tumor progression tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): This application focuses on a novel signaling link that could have significant implications for chemoprevention and personalized therapy for prostate cancer. Specifically, we identified a functional link between the oncogenic kinase PKCε and inducible cyclooxygenase-2 (COX-2). Studies demonstrated a clear association between COX- 2 up-regulation in primary tumors, development of metastasis, and poor patient survival. There is significant evidence that inhibition of COX isoforms with non-steroidal anti-inflammatory drugs reduces risk of human cancers. In addition, COX-2 inhibitors inhibit proliferation and trigger apoptosis in prostate cancer cells, and impair prostate tumor growth in mouse models. PKCε is markedly up-regulated in prostate cancer and other cancers, and it controls key mitogenic/survival pathways such as Erk, Akt, Stat-3 and NF-κB. We generated a prostate-specific transgenic mouse model for PKCε (PB-PKCε), which develops prostatic intraepithelial neoplasia (PIN) lesions. Most remarkably, in a Pten-deficient (+/-) background, PKCε transgenic mice develop invasive prostate adenocarcinomas with Akt and NF-κB hyperactivation, and COX-2 up-regulation. Prostate epithelial cellular models engineered to recapitulate PKCε overexpression and Pten loss (i.e. PI3K hyperactivation) acquire tumorigenic potential in nude mice, become highly invasive, display COX-2 up- regulation and elevated PGE2 production (which has been linked to prostate cancer), and become highly sensitive to the killing effect of a COX-2 inhibitor. In Specific Aim 1 the main goal is to determine if COX-2 mediates PKCε-driven tumorigenesis using a number of approaches, including COX-2 shRNA silencing in PKCε expressing/Pten depleted cells orthotopically implanted in mouse prostates, treatment of PB-PKCε mice with COX-2 inhibitors, and the generation of a mouse model for prostate-specific COX-2 gene deletion in the context of PKCε overexpression. In Specific Aim 2 we will dissect the functional relevance of a link we recently identified between PKCε and the inducible PGE2 synthase mPGES-1. A dual mouse model for prostate specific PKCε overexpression in a mPGES-1-null background will be generated. The role of PGE2 (EP) receptors in driving an autocrine tumorigenic "vicious cycle" will be mechanistically dissected. In Specific Aim 3 we will test the hypothesis that specific p110 PI3K isoforms mediate COX-2/mPGES-1/PGE2 induction in prostate models and the tumorigenic phenotype driven by PKCε overexpression/Pten loss. Finally, to add prognostic and translational value to our studies, in Specific Aim 4 we will take advantage of a large collection of human prostate cancer specimens to determine if correlations exist between PKCε overexpression and COX-2/mPGES-1 induction. Samples with different Gleason grades, disease recurrence after prostatectomy, and castration-resistant (CRPC) disease will be used. In addition to the significant mechanistic, prognostic and therapeutic implications, our studies may provide proof-of-principle for the use of inhibitors of the COX-2/mPGES-1/EP receptor pathway for the prevention and treatment of subsets of prostate cancer patients with defined oncogenic alterations.

描述（应用程序提供）：本应用集中在一种新的信号连接上，该联系可能对化学预防和对前列腺癌的个性化治疗具有重要意义。具体而言，我们确定了致癌激酶PKCε和诱导性环氧酶-2（COX-2）之间的功能联系。研究表明，在原发性肿瘤中，Cox-2上调之间存在明显的关联，转移的发展和患者生存率差。有大量证据表明，用非甾体类抗炎药抑制Cox同工型降低了人类癌症的风险。此外，COX-2抑制剂抑制了前列腺癌细胞中的增殖并触发凋亡，并损害了小鼠模型中的前列腺肿瘤的生长。 PKCε在前列腺癌和其他癌症中明显上调，它控制着关键的有丝分裂/生存途径，例如ERK，AKT，Stat-3和NF-κB。我们生成了PKCε（PB-PKCε）的前列腺特异性转基因小鼠模型，该模型发展为前列腺上皮内肿瘤（PIN）病变。最值得注意的是，在缺乏PTEN的背景（+/-）背景下，PKCε转基因小鼠具有Akt和NF-κB过度激活和COX-2上调的浸润性前列腺腺癌。前列腺上皮细胞模型设计用于概括PKCε过表达和PTEN损失（即PI3K过度激活）在裸鼠中获得肿瘤潜力，变得高度侵入性，显示COX-2上调和PGE2的产生（已与Prostate Cancer具有高度敏感），并具有高度敏感的人，并具有高度的效应，并具有效应的效应。在特定目标1中，主要目标是确定COX-2是否使用多种方法介导PKCε驱动的肿瘤，包括PKCε表达/PTEN DEPTHD细胞中的Cox-2 ShRNA沉默在小鼠Prostates中植入小鼠Prostates中，用PB-PKCε小鼠用Cox-2的cox-ribitors和小鼠模型处理小鼠模型，并将其用于小鼠的cox-spec， PKCε过表达。在特定目标2中，我们将剖析我们最近在PKCε和诱导型PGE2合酶MPGES-1之间识别的链接的功能相关性。将生成MPGES-1-NULL背景中前列腺特异性PKCε过表达的双重小鼠模型。 PGE2（EP）受体在驱动自分泌肿瘤“恶性循环”中的作用将机械解剖。在特定目标3中，我们将测试以下假设：前列腺模型中的特定P110 PI3K同工型中位数COX-2/MPGES-1/PGE2诱导以及由PKCε过表达驱动/PTEN损失驱动的致瘤表型。最后，为了在我们的研究中增加预后和翻译价值，在特定目的4中，我们将利用大量的人类前列腺癌标本来确定PKCε过表达与COX-2/MPGES-1感应之间是否存在相关性。将使用具有不同GLEASON等级的样本，前列腺切除术后疾病复发以及耐castration（CRPC）疾病的样本。除了重要的机械，预后和热含义外，我们的研究还可以为使用COX-2/MPGES-1/EP受体途径的抑制剂提供原则证明，以预防和治疗具有定义的致癌性改变的前列腺癌患者亚群。