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: 7939191
• 负责人: Alan P. Fields
• 金额: $ 16.86万
• 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/7939191
• 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; Protein Kinase C Inhibitor; 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; citrate carrier; 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)：本项目的目标是阐明有助于肺癌启动和维持的蛋白激酶C(PKC)信号机制，并将这些机制见解转化为更好的预后和治疗策略。我们最近发现了非典型的PKC？PRKCI基因是人类在肺中的癌基因。此外，我们还发现小鼠PKC？PrkCi基因在体内致癌Kras诱导肺肿瘤发生的最早步骤中是必需的。具体地说，Prkci是Kras介导的细支气管肺泡干细胞(BASCs)转化所必需的，BASCs是Kras介导的肺肿瘤发生的假定起源细胞。Prkci的基因破坏或PKC9抑制剂金硫马酸(ATM)的治疗，在体内外阻断了Kras介导的BASC的扩张和形态转化，以及体内肺癌的生长。初步结果表明，Kras、Prkci介导的BASCs扩增涉及多梳基因Bmi1的诱导。BMI1是一种表观遗传的染色质修饰物/转录调节因子，与癌症干细胞的识别和自我更新有关。与Prkci一样，Bmi1对于Kras介导的BASC扩张和肺肿瘤的发生也是必需的。基于这些初步数据，我们假设Prkci至少部分地通过激活Bmi1信号通路来驱动Kras介导的BASC转化和肺肿瘤的发生。我们进一步假设，一个类似的PKC？-Bmi1信号轴在人类肺癌干细胞的维持、扩增和致瘤潜能中发挥着关键作用。最后，我们假设ATM将有效地抑制人肺癌干细胞的自我更新和致瘤潜能。我们将通过完成两个相互关联的具体目标来检验这些假设。在目标1中，我们将评估PKC？-Par6-Ect2-rac1信号轴在BASC转化中的作用，并剖析PKC？以及这些细胞中的Bmi1信号。在目标2中，我们将确定PKC的角色？以及Bmi1信号在肺癌干细胞自我更新和肿瘤启动活性中的作用。我们将开发和鉴定一组来自原发肺肿瘤的肺癌干细胞系。这些研究的完成将为致癌PKC？在假定的肺癌干细胞中的信号，加强我们对Kras介导的肺肿瘤发生的理解，并评估一种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有重要的意义。作为治疗靶点，并将ATM用作治疗肺癌的新疗法。 公共卫生相关性：肺癌是美国癌症死亡的头号原因。蛋白激酶C？(PKC？)是肺癌的癌基因、预后标志物和治疗靶点。本项目将阐明PKC？驱动肺癌干细胞生长和肿瘤启动活性的信号机制，并决定一种新的PKC？抑制剂，金硫马酸盐，以阻止肺癌干细胞生长和致瘤性。最后，该项目将从人类肺癌患者中产生新的肺癌干细胞资源。这些组织资源在评估针对这些致命细胞的新疗法方面将是无价的。