Protein Kinase D in oncogenic oxidative stress signaling

致癌氧化应激信号传导中的蛋白激酶 D

• 批准号: 8403781
• 负责人: Peter Storz
• 金额: $ 28.95万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8403781
• 关键词: 1,2-diacylglycerol; Adenocarcinoma Cell; Apoptotic; Binding; Cancer Patient; Cell Death; Cell Nucleus; Cell Survival; Data; Development; Diglycerides; Dose; Enzymes; Equilibrium; Generations; Growth Factor; Homeostasis; In Vitro; Lead; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mitochondria; Mutation; Nature; Oncogenic; Organelles; Outcome; Oxidative Stress; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Phenotype; Phosphorylation; Reactive Oxygen Species; Recruitment Activity; Role; Second Messenger Systems; Signal Transduction; Survival Rate; Testing; Therapeutic; Tumor Suppressor Proteins; Work; base; cancer cell; cancer therapy; cellular targeting; combinatorial; inhibitor/antagonist; neoplastic cell; novel; pancreatic cancer cells; protein kinase D; response; screening; second messenger; sensor; transcription factor

PROJECT/SUMMARY ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is probably the most aggressive form of cancer known to date with the lowest overall 5-year survival rate. Increased growth factor signaling and K-ras mutations in PDAC lead to the generation of reactive oxygen species (ROS) at elevated rates. ROS act as second messengers in intracellular signaling cascades, which induce and maintain the oncogenic phenotype. Little is known about the protective signaling cascades that are activated by oxidative stress and regulate tumor cell survival. It is of great importance to understand these protective signaling mechanisms since their modulation may allow tipping the balance in ROS homeostasis to sensitize cancer cells to chemotherapeutics-induced cell death. It is our hypothesis that oxidative stress mediates tumor cell survival by activating Protein Kinase D. Specifically, we hypothesize that ROS-mediated PKD signaling is transmitted through the mitochondria and that PKD activated by this pathway regulates survival via the transcription factor FOXO3a. We further hypothesize that the pharmacological inhibition of PKD increases the sensitivity of tumor cells to ROS-mediated cell death. To test this we will: Determine how Protein Kinase D is recruited to the mitochondria in response to ROS (Specific Aim 1); Characterize the tumor suppressor FOXO3a as a cellular target for ROS-activated PKD (Specific Aim 2) and Characterize novel PKD inhibitors and their value for cancer therapy (Specific Aim 3). Successful completion of this proposal will contribute to the understanding of ROS- and PKD-mediated protective signaling in PDAC cells. It will show that in response to growth factors, K- ras or other inducers of ROS, as a first step in the PKD activation mechanisms, PKD is located to the mitochondria via DAG binding. It will further dissect PKD's role in tumor cell survival by identifying FOXO3a as a novel PKD target. Finally, we will characterize novel PKD-inhibiting compounds for their value in sensitizing pancreatic cancer cells to ROS- and chemotherapeutics-induced cell death. Overall our results will provide the basis for the development of novel and more potent therapeutic strategies for pancreatic cancer patients.

项目/总结抽象