Integration of Glycolysis with the Epithelial-Mesenchymal Transition

糖酵解与上皮间质转化的整合

基本信息

批准号：
8718440
负责人：
Robert T Spaulding
金额：
$ 3.17万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-07 至 2019-07-06
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8718440
关键词：
6-Phosphofructo-2-kinase 6-Phosphofructokinase A549 Adjuvant Advanced Malignant Neoplasm Binding Boxing Cancer cell line Cell Cycle Cells Cessation of life Characteristics Clinic Clinical Cyclin-Dependent Kinases Data Set Development Disseminated Malignant Neoplasm E-Cadherin Embryonic Development Epithelial Fibronectins Fructose Genes Glycolysis Homeobox In Vitro Invaded KRAS2 gene Lead Maintenance Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Mesenchymal Metastatic Pancreatic Adenocarcinoma Metastatic to Molecular Profiling Mutate Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Oncogenic Operative Surgical Procedures Organ PTEN gene Pancreas Pancreatic Adenocarcinoma Patients Phase I Clinical Trials Phenotype Phosphorylation Play Property Proteins Regulation Resected Resistance Retinoblastoma Retinoblastoma Protein Role STAT3 gene Solid Neoplasm Testing Therapeutic Transcription Repressor/Corepressor Treatment Protocols Up-Regulation Vimentin Xenograft Model Zinc Fingers active method cancer cell cancer stem cell design drug development epithelial to mesenchymal transition fructose 2,6-diphosphate fructose-6-phosphate in vivo inhibitor/antagonist molecular phenotype neoplastic cell novel novel therapeutic intervention overexpression pancreatic cancer cells prevent public health relevance stemness trait transcription factor transcriptomics tumor tumor growth

项目摘要

PROJECT SUMMARY Overexpression of Zinc finger E-box binding homeobox 1 (ZEB1) in tumor cells promotes the epithelial- mesenchymal transition (EMT) that is associated with enhanced invasive and metastatic capabilities and the acquisition of cancer-stem cell characteristics. Understanding how ZEB1 is regulated should permit the identification of druggable targets that can be exploited for the treatment of metastatic cancers that over- express ZEB1, including pancreatic and non-small cell lung cancers (NSCLC). The HIF-1¿-inducible 6- phosphofructo-2-kinase/fructose-2,6-bisphosphase-3 (PFKFB3) is over-expressed in tumors, activates glycolysis via its product fructose-2,6-bisphosphate and was recently found to be an activator of cyclin- dependent kinases (Cdks). Given the accumulating evidence suggesting a role for cell cycle regulators such as the Cdks in the EMT, we postulated that PFKFB3 may be essential for the acquisition/maintenance of mesenchymal traits in tumor cells. In preliminary studies, we demonstrate that PFKFB3 silencing in A549 NSCLC cells and MIA PaCa-2 pancreatic cancer cells causes a marked decrease in ZEB1 expression and reverses the EMT, as assessed by increased E-cadherin (an epithelial marker) and decreased vimentin/fibronectin (mesenchymal markers) levels. We further show that knockdown of PFKFB3 decreases the phosphorylation of the retinoblastoma (RB) protein, a Cdk target, and the expression of the STAT3 protein, both of which have recently been found to regulate ZEB1 expression. We therefore hypothesize that upregulation of PFKFB3 in tumor cells increases ZEB1 expression via an RB and/or STAT3-dependent mechanism, leading to the acquisition/maintenance of a mesenchymal phenotype associated with increased metastatic ability and stemness. The following specific aims will be pursued to test this hypothesis: (1) To study the functional interaction of PFKFB3 with ZEB1 and its effect on invasion and cancer stem cell properties in vitro; and (2) To examine the functional interaction of PFKFB3 with ZEB1 in the progression of metastatic pancreatic adenocarcinoma in vivo. At the end of these studies, we expect to have established a novel function for PFKFB3 in the regulation of the ZEB1 gene and EMT, which may have therapeutic implications for the treatment of aggressive, metastatic cancers such as pancreatic adenocarcinoma.

项目概要肿瘤细胞中锌指 E 盒结合同源盒 1 (ZEB1) 的过度表达可促进上皮细胞间质转化（EMT）与增强的侵袭和转移能力以及了解 ZEB1 的调控方式应该有助于了解癌症干细胞的特性。鉴定可用于治疗过度转移性癌症的药物靶标表达 ZEB1，包括胰腺癌和非小细胞肺癌 (NSCLC)。 -诱导型6- 磷酸果糖-2-激酶/果糖-2,6-双磷酸-3 (PFKFB3) 在肿瘤中过度表达，激活通过其产物果糖-2,6-二磷酸进行糖酵解，最近发现它是细胞周期蛋白的激活剂鉴于越来越多的证据表明细胞周期调节剂的作用，例如 EMT 中的 Cdks，我们发布了 PFKFB3 对于获取/维护在初步研究中，我们证明 A549 中 PFKFB3 沉默。 NSCLC细胞和MIA PaCa-2胰腺癌细胞导致ZEB1表达显着下降并逆转 EMT（通过 E-钙粘蛋白（上皮标记物）增加和减少来评估）我们进一步表明，PFKFB3 的敲低会降低波形蛋白/纤连蛋白（间充质标记物）水平。视网膜母细胞瘤 (RB) 蛋白（Cdk 靶标）的磷酸化以及 STAT3 蛋白的表达，最近发现这两者都可以调节ZEB1的表达。肿瘤细胞中 PFKFB3 的上调通过 RB 和/或 STAT3 依赖性增加 ZEB1 表达机制，导致获得/维持与增加相关的间充质表型转移能力和干性将追求以下具体目标来检验这一假设：（1）研究 PFKFB3 与 ZEB1 的功能相互作用及其对侵袭和癌症干细胞特性的影响 (2) 检查 PFKFB3 与 ZEB1 在转移性进展中的功能相互作用在这些研究结束时，我们期望建立一种新的功能。 PFKFB3 对 ZEB1 基因和 EMT 的调节，这可能对治疗侵袭性、转移性癌症，例如胰腺癌。