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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：
10543367
负责人：
MARCELO G. KAZANIETZ
金额：
$ 3.55万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10543367
关键词：
Animals Apoptosis Automobile Driving Breast Cancer Burden Cancer Cell Growth Cancer Patient Carcinoma Castration Cell model Cells Chemoprevention Chemopreventive Agent Collection Colon Carcinoma Development Diagnosis Dinoprostone Disease Disease Progression Effectiveness Engineering Enzymes Ep-1 Epidemiology Epithelial Epithelial Cells Gene Deletion Gene Proteins Generations Genes Genetically Engineered Mouse Gleason Grade for Prostate Cancer Goals Growth Head and Neck Cancer Human Impairment Implant Individual Laboratories Lead Lesion Link Lung Maintenance Malignant Neoplasms Malignant neoplasm of prostate Mediating Modeling Mus Mutation Neoplasm Metastasis Non-Steroidal Anti-Inflammatory Agents Nude Mice Oncogenic Pathology Pathway interactions Patients Pharmacology Phenotype Phosphotransferases Play Prevention Primary Neoplasm Production Prostaglandin Production Prostaglandins Prostate Prostate Adenocarcinoma Prostate Cancer therapy Prostatectomy Prostatic Intraepithelial Neoplasias Prostatic Neoplasms Protein Isoforms Protein Kinase C Protein Overexpression Recurrence 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 design in vivo inhibitor migration mouse PGE synthase 1 mouse model novel overexpression patient subsets personalized medicine prevent prognostic prostate cancer cell prostate cancer progression prostate lesions protein kinase C epsilon protein kinase C kinase 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（由申请人提供）：本申请关注一种新型信号传导连接，其可能对前列腺癌的化学预防和个性化治疗具有重要意义。具体来说，我们确定了致癌激酶PKCε和诱导型环氧合酶-2（考克斯-2）之间的功能联系。研究表明原发性肿瘤中考克斯- 2的上调、转移的发展和患者生存率差之间存在明确的相关性。有显著的证据表明，用非甾体抗炎药抑制考克斯亚型可降低人类癌症的风险。此外，考克斯-2抑制剂抑制前列腺癌细胞的增殖并引发细胞凋亡，并损害小鼠模型中的前列腺肿瘤生长。PKCε在前列腺癌和其他癌症中显著上调，并且其控制关键的促有丝分裂/存活途径，如Erk、Akt、Stat-3和NF-κB。我们建立了前列腺特异性PKCε转基因小鼠模型（PB-PKCε），该模型可发生前列腺上皮内瘤变（PIN）病变。最值得注意的是，在Pten缺陷（+/-）背景下，PKCε转基因小鼠发生侵袭性前列腺癌，Akt和NF-κB过度活化，考克斯-2上调。经工程改造以重现PKCε过表达和Pten损失（即PI 3 K过度活化）的前列腺上皮细胞模型在裸鼠中获得致瘤潜力，变得高度侵袭性，显示考克斯-2上调和升高的PGE 2产生（其与前列腺癌相关），并且变得对考克斯-2抑制剂的杀伤作用高度敏感。在特定目标1中，主要目标是使用多种方法确定考克斯-2是否介导PKCε驱动的肿瘤发生，包括原位植入小鼠前列腺的PKCε表达/Pten耗竭细胞中的考克斯-2 shRNA沉默、用考克斯-2抑制剂治疗PB-PKCε小鼠以及在PKCε过表达背景下产生前列腺特异性考克斯-2基因缺失的小鼠模型。在《特定目标2》中，我们将剖析我们最近发现的PKCε和诱导型PGE 2合酶mPGES-1之间的联系的功能相关性。将生成mPGES-1空白背景下前列腺特异性PKCε过表达的双小鼠模型。PGE 2（EP）受体在驱动自分泌致瘤“恶性循环”中的作用将被机械地剖析。在特定目标3中，我们将检验以下假设：在前列腺模型中，特定p110 PI 3 K亚型介导考克斯-2/mPGES-1/PGE 2诱导，以及PKCε过表达/Pten丢失驱动的致瘤表型。最后，为了增加我们研究的预后和转化价值，在特定目标4中，我们将利用大量的人前列腺癌标本来确定PKCε过表达和考克斯-2/mPGES-1诱导之间是否存在相关性。将使用具有不同Gleason分级、子宫切除术后疾病复发和去势抵抗性（CRPC）疾病的样本。除了显著的机制、预后和治疗意义外，我们的研究还可以为使用考克斯-2/mPGES-1/EP受体通路抑制剂预防和治疗具有明确致癌改变的前列腺癌患者亚群提供原理证明。