Cell signaling pathways are important in ferroptosis

细胞信号通路在铁死亡中很重要

基本信息

  • 批准号:
    10747174
  • 负责人:
  • 金额:
    $ 3.54万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-07-01 至 2025-06-30
  • 项目状态:
    未结题

项目摘要

ABSTRACT Colorectal cancer (CRC) can be effectively treated if detected early. However, most tumors are detected at an advanced stage when treatment options are limited. There has been a resurgence in assessing altered cell metabolism in cancer growth. Unlike normal cells, cancer cells rely mainly on aerobic glycolysis for ATP production. Aerobic glycolysis is inefficient in ATP generation, but the glycolytic and TCA cycle intermediates are rerouted for the production of biomass. These studies have led to identification of several critical pathways that have the potential to be therapeutic targets. Currently, much less is known about the contribution of micronutrient metabolism in cancer. Our recent work has established that iron accumulation is critical step in the growth and progression of colon cancer. Colon cancer cells are addicted to high iron levels for cell proliferation. We have clearly shown that there is an accumulation of intra-tumoral iron compared to adjacent normal mucosa. Genetic or dietary restriction of iron leads to a robust decrease in tumor proliferation and progression. However, it is unclear how cancer cells maintain high iron levels, resistant to iron-mediated oxidative toxicity and utilize iron for signaling, survival, and growth. Our goals are to identify mechanism underlying these major gaps to lay the foundation for iron-based therapies in colon cancer. We hypothesize that CRCs bypass the toxicities of high iron accumulation to fuel oncogenic signaling. Cellular iron levels are regulated via a hepatic hormone hepcidin. Hepcidin binds to an iron exporter ferroportin leading to degradation and inhibition of iron export. We show that colon tumor epithelium express high levels of hepcidin and low ferroportin. Aim 1 will delineate if hepcidin/ferroportin axis is the major mechanism leading to iron accumulation and if it can be targeted for therapy. Iron is essential for growth but can be highly toxic to a cell. Iron levels need to be tightly controlled. Iron via the Fenton reaction leads to high superoxide formation and initiates a form of non-apoptotic cell death called ferroptosis. Our recent data suggest that CRCs actively suppress ferroptosis. Aim 2 will understand mechanisms leading to resistance of iron induced damage. In Aim 3 we will address why CRCs need high levels of iron to maintain growth. Our previous work showed that iron can directly activate oncogenic kinases through a putative posttranslational modification we termed ferritinylation. In this Aim we plan to explore the importance of ferritinylation using cell models and patient-derived organoid models. Accomplishing these Aims will (i) uncover mechanisms of iron accumulation (ii) define novel iron related vulnerabilities, and (iii) characterize how iron drives oncogenic signaling in CRC. These studies will also highlight new pathways, genetic vulnerabilities and drug targets for CRC.
摘要 结直肠癌(CRC)如果早期发现,可以有效治疗。然而,大多数肿瘤是在 晚期,治疗选择有限。在评估改变了的 在癌症生长中的细胞代谢。与正常细胞不同,癌细胞主要依靠有氧糖酵解获得ATP 生产有氧糖酵解在ATP生成中是无效的,但糖酵解和TCA循环 中间体被改道用于生产生物质。这些研究导致了几种 关键途径,有可能成为治疗靶点。目前,对这一问题的了解要少得多。 微量营养素代谢在癌症中的作用。我们最近的研究表明铁的积累 是结肠癌生长和发展的关键步骤。结肠癌细胞对高铁上瘾 细胞增殖的水平。我们已经清楚地表明,有一个积累的肿瘤内铁 与邻近的正常粘膜相比。铁的遗传或饮食限制导致铁的强烈减少, 肿瘤增殖和进展。然而,目前还不清楚癌细胞如何维持高铁水平, 抗铁介导的氧化毒性,并利用铁信号,生存和生长。我们的目标是 确定这些主要差距的机制,为结肠铁基疗法奠定基础 癌我们假设CRCs绕过了高铁积累的毒性, 发信号。细胞铁水平通过肝激素铁调素调节。铁调素与铁结合 输出者膜铁转运蛋白导致降解和抑制铁输出。我们发现结肠肿瘤 上皮表达高水平铁调素和低水平的铁转运蛋白。目标1将描述铁调素/铁转运蛋白 轴是导致铁积累的主要机制,以及是否可以靶向治疗。铁是 对生长是必需的,但对细胞具有高度毒性。铁的含量需要严格控制。铁通过 芬顿反应导致高的超氧化物的形成,并启动一种形式的非凋亡细胞死亡,称为 铁性下垂我们最近的数据表明,CRCs积极抑制铁凋亡。Aim 2会理解的 导致铁诱导的损伤的抗性的机制。在目标3中,我们将讨论为什么CRC需要高 铁的水平,以保持增长。我们以前的工作表明,铁可以直接激活致癌基因, 我们称之为铁蛋白酰化。在这个目标中,我们计划 使用细胞模型和患者来源的类器官模型探索铁蛋白化的重要性。 实现这些目标将(i)揭示铁积累的机制(ii)定义新的铁 相关的脆弱性,和(iii)表征铁如何驱动致癌信号在CRC。这些研究 还将强调新的途径,遗传脆弱性和CRC的药物靶点。

项目成果

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YATRIK M SHAH其他文献

YATRIK M SHAH的其他文献

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{{ truncateString('YATRIK M SHAH', 18)}}的其他基金

Understanding the mechanisms of iron addiction in colon cancer
了解结肠癌铁成瘾的机制
  • 批准号:
    10653978
  • 财政年份:
    2020
  • 资助金额:
    $ 3.54万
  • 项目类别:
Understanding the mechanisms of iron addiction in colon cancer
了解结肠癌铁成瘾的机制
  • 批准号:
    10199967
  • 财政年份:
    2020
  • 资助金额:
    $ 3.54万
  • 项目类别:
Understanding the mechanisms of iron addiction in colon cancer
了解结肠癌铁成瘾的机制
  • 批准号:
    10442709
  • 财政年份:
    2020
  • 资助金额:
    $ 3.54万
  • 项目类别:
Control of iron absorption by intestinal HIF2 in iron and hematological disorders
铁和血液系统疾病中肠道 HIF2 控制铁吸收
  • 批准号:
    10296193
  • 财政年份:
    2012
  • 资助金额:
    $ 3.54万
  • 项目类别:
Control of iron absorption by intestinal HIF2 in iron and hematological disorders
铁和血液系统疾病中肠道 HIF2 控制铁吸收
  • 批准号:
    8275309
  • 财政年份:
    2012
  • 资助金额:
    $ 3.54万
  • 项目类别:
Control of iron absorption by intestinal HIF2 in iron and hematological disorders
铁和血液系统疾病中肠道 HIF2 控制铁吸收
  • 批准号:
    8607546
  • 财政年份:
    2012
  • 资助金额:
    $ 3.54万
  • 项目类别:
Control of iron absorption by intestinal HIF2 in iron and hematological disorders
铁和血液系统疾病中肠道 HIF2 控制铁吸收
  • 批准号:
    9176092
  • 财政年份:
    2012
  • 资助金额:
    $ 3.54万
  • 项目类别:
Control of iron absorption by intestinal HIF2 in iron and hematological disorders
铁和血液系统疾病中肠道 HIF2 控制铁吸收
  • 批准号:
    10456492
  • 财政年份:
    2012
  • 资助金额:
    $ 3.54万
  • 项目类别:
Control of iron absorption by intestinal HIF2 in iron and hematological disorders
铁和血液系统疾病中肠道 HIF2 控制铁吸收
  • 批准号:
    10456204
  • 财政年份:
    2012
  • 资助金额:
    $ 3.54万
  • 项目类别:
Control of iron absorption by intestinal HIF2 in iron and hematological disorders
铁和血液系统疾病中肠道 HIF2 控制铁吸收
  • 批准号:
    8824526
  • 财政年份:
    2012
  • 资助金额:
    $ 3.54万
  • 项目类别:

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