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: 8244684
• 负责人: Alan P. Fields
• 金额: $ 8.42万
• 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/8244684
• 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; self-renewal; stem; stem cell niche; therapeutic target; tissue resource; tool; treatment strategy; tumor; tumor growth; tumorigenic

Project Summary 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 PKCi gene PRKCI as a human oncogene in the lung. Furthermore, we find that the mouse PKCi 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 PKC¿ 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 PKCi-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 PKCi-Par6-Ect2-Rac1 signaling axis in BASC transformation and dissect the mechanism of crosstalk between PKCi and Bmi1 signaling in these cells. In Aim 2 we will determine the role of PKCi 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 PKCi 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 PKCi as a therapeutic target and for the use of ATM as a novel therapeutic for the treatment of lung cancer.

项目概要 该项目的目标是阐明有助于肺功能的蛋白激酶 C (PKC) 信号传导机制。 癌症的发生和维持，并将这些机制见解转化为更好的预后和治疗 策略。我们最近将非典型 PKCi 基因 PRKCI 鉴定为人类肺部致癌基因。 此外，我们发现小鼠 PKCi 基因 Prkci 是肺的最早步骤所必需的。 体内致癌Kras诱导的肿瘤发生。具体来说，Prkci 对于 Kras 介导是必要的 支气管肺泡干细胞 (BASC) 的转化，这是 Kras 介导的肺的假定起源细胞 肿瘤发生。 Prkci 的基因破坏或用 PKC¿ 抑制剂金硫苹果酸 (ATM) 治疗可阻断 Kras介导的BASC体外和体内扩增和形态转化以及肺肿瘤 体内生长。初步结果表明 Kras、Prkci 介导的 BASC 扩增涉及诱导 多梳基因 Bmi1。 Bmi1 是一种表观遗传染色质修饰剂/转录调节因子 癌症干细胞的身份和自我更新。与 Prkci 一样，Bmi1 对于 Kras 介导的 BASC 扩展是必需的 和肺部肿瘤的发生。根据这些初步数据，我们假设 Prkci 驱动 Kras 介导 BASC 转化和肺肿瘤发生，至少部分是通过 Bmi1 信号传导的激活 途径。我们进一步假设类似的 PKCi-Bmi1 信号轴在 人肺癌干细胞的维持、扩增和致瘤潜力。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具体目标来检验这些假设。在目标 1 中，我们将评估角色 BASC转化中PKCi-Par6-Ect2-Rac1信号轴的研究并剖析串扰机制 这些细胞中 PKCi 和 Bmi1 信号传导之间的关系。在目标 2 中，我们将确定 PKCi 和 Bmi1 的作用 肺癌干细胞自我更新和肿瘤启动活性中的信号传导。我们将开发和 表征一组来自原发性肺肿瘤的肺癌干细胞系。完成这些研究将 为假定的肺癌干细胞中致癌 PKCi 信号传导提供重要的新机制见解， 增强我们对 Kras 介导的肺部肿瘤发生的理解，并评估一种新型药物的功效 针对肺癌干细胞中关键致癌途径的治疗剂。这些研究有 对于 PKCi 作为治疗靶点以及使用 ATM 作为新型治疗药物具有重要意义 肺癌的治疗。