Atypical PKC signaling in lung cancer stem cells

肺癌干细胞中的非典型 PKC 信号传导

基本信息

  • 批准号:
    8244684
  • 负责人:
  • 金额:
    $ 8.42万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Alan P. Fields其他文献

Activation of Na/H exchanger in mesangial cells is associated with translocation of PKC isoforms.
系膜细胞中 Na/H 交换器的激活与 PKC 亚型的易位相关。
  • DOI:
    10.1152/ajprenal.1993.265.1.f53
  • 发表时间:
    1993
  • 期刊:
  • 影响因子:
    0
  • 作者:
    R. Saxena;B. A. Saksa;Alan P. Fields;M. B. Ganz
  • 通讯作者:
    M. B. Ganz
A Role for Nuclear Phosphatidylinositol-specific Phospholipase C in the G<sub>2</sub>/M Phase Transition
  • DOI:
    10.1074/jbc.272.42.26313
  • 发表时间:
    1997-10-17
  • 期刊:
  • 影响因子:
  • 作者:
    Bin Sun;Nicole R. Murray;Alan P. Fields
  • 通讯作者:
    Alan P. Fields

Alan P. Fields的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Alan P. Fields', 18)}}的其他基金

Investigating cells of origin and oncogenic modifiers of 3q26-driven LUSC
研究 3q26 驱动的 LUSC 的起源细胞和致癌修饰因子
  • 批准号:
    10593501
  • 财政年份:
    2021
  • 资助金额:
    $ 8.42万
  • 项目类别:
A Genetically Tractable Mouse Model for PRKCI-driven Lung Squamous Cell Carcinoma
PRKCI 驱动的肺鳞状细胞癌的遗传易控制小鼠模型
  • 批准号:
    10653913
  • 财政年份:
    2021
  • 资助金额:
    $ 8.42万
  • 项目类别:
A Genetically Tractable Mouse Model for PRKCI-driven Lung Squamous Cell Carcinoma
PRKCI 驱动的肺鳞状细胞癌的遗传易控制小鼠模型
  • 批准号:
    10296271
  • 财政年份:
    2021
  • 资助金额:
    $ 8.42万
  • 项目类别:
A Genetically Tractable Mouse Model for PRKCI-driven Lung Squamous Cell Carcinoma
PRKCI 驱动的肺鳞状细胞癌的遗传易控制小鼠模型
  • 批准号:
    10413236
  • 财政年份:
    2021
  • 资助金额:
    $ 8.42万
  • 项目类别:
Therapeutic targeting of Kras-driven Lung Adenocarcinoma
Kras 驱动的肺腺癌的治疗靶向
  • 批准号:
    9303312
  • 财政年份:
    2016
  • 资助金额:
    $ 8.42万
  • 项目类别:
The pathophysiology and palliation of the paclitaxel-induced acute pain syndrome
紫杉醇诱发的急性疼痛综合征的病理生理学和缓解作用
  • 批准号:
    8930932
  • 财政年份:
    2014
  • 资助金额:
    $ 8.42万
  • 项目类别:
Combined PKCiota and mTOR inhibition for treatment of advanced squamous lung canc
联合 PKCiota 和 mTOR 抑制治疗晚期鳞状肺癌
  • 批准号:
    8299006
  • 财政年份:
    2011
  • 资助金额:
    $ 8.42万
  • 项目类别:
Combined PKCiota and mTOR inhibition for treatment of advanced squamous lung canc
联合 PKCiota 和 mTOR 抑制治疗晚期鳞状肺癌
  • 批准号:
    8110919
  • 财政年份:
    2011
  • 资助金额:
    $ 8.42万
  • 项目类别:
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
  • 财政年份:
    2010
  • 资助金额:
    $ 8.42万
  • 项目类别:
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
  • 财政年份:
    2010
  • 资助金额:
    $ 8.42万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了