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: 8598858
• 负责人: Peter Storz
• 金额: $ 29.87万
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8598858
• 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/摘要摘要 胰腺导管腺癌(PDAC)可能是迄今为止已知的最具侵袭性的癌症。 总体5年生存率最低。PDAC中生长因子信号转导和K-ras突变增加导致 以较高的速率产生活性氧物种(ROS)。RO充当第二信使 细胞内信号级联，诱导和维持致癌表型。人们对此知之甚少 由氧化应激激活的保护性信号级联，调节肿瘤细胞的存活。它是 理解这些保护性信号机制非常重要，因为它们的调制可能会使 打破ROS动态平衡，使癌细胞对化疗药物诱导的细胞死亡敏感。它是 我们的假设是，氧化应激通过激活蛋白激酶D来调节肿瘤细胞的存活。 具体来说，我们假设ROS介导的PKD信号是通过线粒体传递的 由该途径激活的PKD通过转录因子FOXO3a调节生存。我们 进一步假设PKD的药理抑制增加了肿瘤细胞的敏感性 到ROS介导的细胞死亡。为了测试这一点，我们将：确定蛋白激酶D是如何被招募到 线粒体对ROS的反应(特定目标1)；将肿瘤抑制因子FOXO3a描述为细胞 ROS激活的PKD的靶点(特异靶2)、新型PKD抑制剂的表征及其在治疗中的价值 癌症治疗(特定目标3)。成功完成这项建议将有助于理解 ROS和PKD介导的PDAC细胞保护性信号。它将表明，在对增长因素的反应中，K- RAS或其他ROS诱导剂，作为PKD激活机制的第一步，PKD定位于 线粒体通过DAG结合。它将通过确认FOXO3a是 一种新的PKD靶标。最后，我们将表征新的PKD抑制化合物在致敏方面的价值。 胰腺癌细胞对ROS和化疗药物诱导的细胞死亡。总体而言，我们的结果将提供 为胰腺癌患者开发新的、更有效的治疗策略奠定了基础。

项目成果

Targeting protein kinase C subtypes in pancreatic cancer.

• DOI: 10.1586/14737140.2015.1003810
• 发表时间: 2015-04
• 期刊: Expert review of anticancer therapy
• 影响因子: 3.3
• 作者: Storz P

Osteopontin is a multi-faceted pro-tumorigenic driver for central nervous system lymphoma.

• DOI: 10.18632/oncotarget.8537
• 发表时间: 2016-05-31
• 期刊: Oncotarget
• 作者: Yushi Q;Li Z;Von Roemeling CA;Doeppler H;Marlow LA;Kim BY;Radisky DC;Storz P;Copland JA;Tun HW
• 通讯作者: Tun HW

Protein kinase D-mediated phosphorylation at Ser99 regulates localization of p21-activated kinase 4.

• DOI: 10.1042/bj20130281
• 发表时间: 2013-10-15
• 期刊: The Biochemical journal
• 作者: Bastea LI;Döppler H;Pearce SE;Durand N;Spratley SJ;Storz P
• 通讯作者: Storz P