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.

项目总结