Atypical PKC signaling in lung cancer stem cells

肺癌干细胞中的非典型 PKC 信号传导

• 批准号: 8100459
• 负责人: Alan P. Fields
• 金额: $ 19.62万
• 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: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8100459
• 关键词: Alveolar; Aurothiomalate; Behavior; Cancer Etiology; Cancer Patient; Cell Line; Cells; Cessation of life; Chromatin; Data; Epigenetic Process; Exhibits; Genes; Genetic; Goals; Growth; Homologous Gene; Human; Human Resources; In Vitro; Lung; Lung Adenocarcinoma; Lung Neoplasms; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Mouse Protein; Non-Small-Cell Lung Carcinoma; Oncogenes; Oncogenic; Pathway interactions; Patients; Play; Polycomb; Process; Prognostic Marker; Property; Protein Kinase; Protein Kinase C; Role; Signal Pathway; Signal Transduction; Squamous Cell Lung Carcinoma; Stem cells; Testing; Therapeutic Agents; Transgenic Mice; Translating; Tumor-Derived; Tumorigenicity; United States; atypical protein kinase C; base; cancer initiation; cancer stem cell; cell growth; cell transformation; genetic manipulation; in vivo; in vivo Model; inhibitor/antagonist; insight; lung tumorigenesis; new therapeutic target; novel; novel therapeutics; prognostic; public health relevance; self-renewal; stem; stem cell niche; therapeutic target; tissue resource; tool; treatment strategy; tumor; tumor growth; tumorigenic

DESCRIPTION (provided by applicant): The goals of this project are to elucidate protein kinase C (PKC) signaling mechanisms that contribute to lung cancer initiation and maintenance and translate these mechanistic insights into better prognostic and treatment strategies. We recently identified the atypical PKC? gene PRKCI as a human oncogene in the lung. Furthermore, we find that the mouse PKC? gene Prkci is required for the very earliest steps of lung tumorigenesis induced by oncogenic Kras in vivo. Specifically, Prkci is necessary for Kras-mediated transformation of bronchio-alveolar stem cells (BASCs), the putative cell of origin of Kras-mediated lung tumorigenesis. Genetic disruption of Prkci, or treatment with the PKC9 inhibitor aurothiomalate (ATM), blocks Kras-mediated expansion and morphological transformation of BASC in vitro and in vivo, and lung tumor growth in vivo. Preliminary results suggest that Kras-, Prkci-mediated expansion of BASCs involves induction of the polycomb gene Bmi1. Bmi1 is an epigenetic chromatin modifier/transcriptional regulator implicated in cancer stem cell identity and self-renewal. Like Prkci, Bmi1 is necessary for Kras-mediated BASC expansion and lung tumorigenesis. Based on these preliminary data, we hypothesize that Prkci drives Kras-mediated BASC transformation and lung tumorigenesis, at least in part, through activation of the Bmi1 signaling pathway. We further hypothesize that a similar PKC?-Bmi1 signaling axis plays a critical role in the maintenance, expansion and tumorigenic potential of human lung cancer stem cells. Finally, we hypothesize that ATM will effectively inhibit the self-renewal and tumorigenic potential of human lung cancer stem cells. We will test these hypotheses through completion of two interrelated specific aims. In Aim 1 we will assess the role of the PKC?-Par6-Ect2-Rac1 signaling axis in BASC transformation and dissect the mechanism of crosstalk between PKC? and Bmi1 signaling in these cells. In Aim 2 we will determine the role of PKC? and Bmi1 signaling in the self-renewal and tumor initiating activity of lung cancer stem cells. We will develop and characterize a panel of lung cancer stem cell lines from primary lung tumors. Completion of these studies will provide important new mechanistic insight into oncogenic PKC? signaling in putative lung cancer stem cells, enhance our understanding of Kras-mediated lung tumorigenesis, and assess the efficacy of a novel therapeutic agent that targets a critical oncogenic pathway in lung cancer stem cells. These studies have important implications for PKC? as a therapeutic target and for the use of ATM as a novel therapeutic for the treatment of lung cancer. PUBLIC HEALTH RELEVANCE: Lung cancer is the number one cause of cancer death in the United States. Protein kinase C??(PKC?) is an oncogene, prognostic marker and therapeutic target in lung cancer. This project will elucidate PKC? signaling mechanisms that drive lung cancer stem cell growth and tumor-initiating activity, and determine the efficacy of a novel PKC? inhibitor, aurothiomalate, to block lung cancer stem cell growth and tumorigenicity. Finally, this project will generate novel lung cancer stem cell resources from human lung cancer patients. These tissue resources will be invaluable in the assessment of novel therapeutics targeting these deadly cells.

描述（由申请人提供）：该项目的目标是阐明有助于肺癌启动和维护的蛋白激酶C（PKC）信号传导机制，并将这些机械洞察力转化为更好的预后和治疗策略。我们最近确定了非典型PKC？ Gene Prkci是肺中的人类癌基因。此外，我们发现鼠标PKC？基因PRKCI是由体内致癌性KRAS诱导的肺肿瘤发生的最早步骤所必需的。具体而言，PRKCI对于KRAS介导的支气管 - 肺泡干细胞（BASC）的转化是必不可少的，这是KRAS介导的肺肿瘤发生的假定起源细胞。 PRKCI的遗传破坏，或用PKC9抑制剂耳催化剂（ATM）治疗，阻止KRAS介导的BASC体外和体内BASC的扩张和形态转化，体内肺肿瘤生长。初步结果表明，prkci介导的BASC的扩展涉及诱导Polycomb基因BMI1。 BMI1是一种表观遗传染色质修饰剂/转录调节剂，与癌症干细胞同一性和自我更新有关。像Prkci一样，BMI1对于KRAS介导的BASC扩张和肺肿瘤发生也是必需的。基于这些初步数据，我们假设PRKCI驱动KRAS介导的BASC转化和肺肿瘤发生，至少部分通过激活BMI1信号通路。我们进一步假设类似的PKC？-BMI1信号轴在人肺癌干细胞的维持，扩张和致瘤潜力中起着至关重要的作用。最后，我们假设ATM将有效抑制人肺癌干细胞的自我更新和致瘤潜力。我们将通过完成两个相互关联的特定目标来检验这些假设。在AIM 1中，我们将评估PKC？-PAR6-ECT2-RAC1信号轴在BASC转换中的作用，并剖析PKC之间的串扰机理？这些细胞中的BMI1信号传导。在AIM 2中，我们将确定PKC的作用？和BMI1信号传导在肺癌干细胞的自我更新和肿瘤引发活性中。我们将开发并表征来自原发性肺肿瘤的肺癌干细胞系。这些研究的完成将为致癌PKC提供重要的新机械洞察力吗？假定的肺癌干细胞中的信号传导，增强了我们对KRAS介导的肺肿瘤发生的理解，并评估了针对肺癌干细胞中关键致癌途径的新型治疗剂的疗效。这些研究对PKC具有重要意义？作为治疗靶标，并将其用作ATM作为治疗肺癌的新型治疗方法。 公共卫生相关性：肺癌是美国癌症死亡的第一大原因。蛋白激酶C ??（PKC？）是肺癌中的癌基因，预后标记和治疗靶标。这个项目会阐明PKC吗？促进肺癌干细胞生长和肿瘤发射活性的信号传导机制，并确定新型PKC的功效？抑制剂，aurothiomalate，以阻断肺癌干细胞的生长和肿瘤性。最后，该项目将产生人类肺癌患者的新型肺癌干细胞资源。这些组织资源在评估针对这些致命细胞的新型治疗剂方面将是无价的。