The Impact of Mitochondrial Repression and Lipid Accumulation by HIF on Tumor Growth

HIF 抑制线粒体和脂质积累对肿瘤生长的影响

基本信息

  • 批准号:
    9976465
  • 负责人:
  • 金额:
    $ 76.29万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-08-01 至 2022-07-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): The frequently altered expression of metabolism genes in solid tumors such as clear cell renal cell cancer (ccRCC) has reinforced the importance of dysregulated metabolism in driving tumor expansion. Indeed, constitutive activation of the hypoxia inducible transcription factor (HIF) through mutations in the von Hippel Lindau (VHL) tumor suppressor gene or through exposure to hypoxia, results in enhanced glucose uptake, glycolytic flux, lactate secretion and suppression of mitochondrial activity. Conversely, reactive oxygen species produced by the mitochondria stimulate HIF-dependent transcription, creating an intricate signaling loop that balances mitochondrial oxygen consumption with the cellular response to hypoxia. In addition to stimulating glycolysis while suppressing OXPHOS, hypoxia has also been demonstrated to stimulate de novo lipogenesis through reductive glutamine metabolism, although it has not yet known how this reductive glutamine metabolism contributes to lipid accumulation in solid tumors and the clear cell phenotype in ccRCC. Importantly, HIF-dependent metabolic changes have been exploited therapeutically, indicating that a more comprehensive understanding of HIF regulated metabolism may yield novel anti-cancer therapies. Oxidative metabolism, which broadly encompasses carbohydrate oxidation, glutamine oxidation, and fatty acid ß-oxidation, is controlled by a number of nuclear and mitochondrial transcription factors that together promote the biogenesis and enzymatic function of mitochondria and is often found repressed in many tumors including ccRCC. First identified for their role in promoting adaptive thermogenesis, the peroxisome proliferator activated receptor gamma coactivators PGC-1 and PGC-1ß promote mitochondrial biogenesis and OXPHOS activity in a wide range of tissues by stimulating the transcriptional activation potential of a number of nuclear transcription factors. PGC-1 and PGC-1ß are encoded by discrete genetic loci and exhibit both distinct and redundant transcriptional targets. Indeed, PGC-1 -/- mice exhibit multi-tissue defects in oxidative metabolism, indicating unique functions for PGC-1 that cannot be compensated for by PGC-1ß. Furthermore, PGC-1 deficient mice accumulate significantly more body fat than wild type mice, and develop fasting induced hepatic steatosis, suggesting an important role for PGC-1 in the regulation of lipid metabolism. While the functions of the PGC family have been extensively studied in normal physiology, their function in the context of malignancy has not been rigorously investigated. Our recent studies indicate that PGC-1 is suppressed in ccRCC through a HIF-/Dec1 transcriptional axis. The suppression of PGC-1 in VHL-wild type renal proximal tubule cells is associated with reduced mitochondrial activity and acquisition of the clear cell (lipid and glycogen accumulation) phenotype, a histological hallmark of ccRCC. These findings provide the first evidence linking the clear cell phenotype to multiple aspects of renal tumorigenesis and raise the potential for PGC-1 stimulation as a novel therapeutic modality in the treatment of renal cell carcinoma, and potentially other solid tumors. The goals of this grant are to explore the molecular mechanisms governing lipid homeostasis in cancer, characterize their contribution to tumorigenesis and identify ways that they can be therapeutically targeted in solid tumors and determine how to best exploit them therapeutically.


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)

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Amato J. Giaccia其他文献

Benzamides substitués et leurs utilisations
苯甲酰胺替代品和用途
  • DOI:
  • 发表时间:
    2011
  • 期刊:
  • 影响因子:
    0
  • 作者:
    M. Bonnet;Denise A. Chan;Amato J. Giaccia;Michael Patrick Hay;Edwin W. Lai;Olga V. Razorenova;Connie Sun;Ray Tabibiazar;Po
  • 通讯作者:
    Po
88: Lysyl Oxidase Is Essential for Hypoxia-Induced Metastasis
  • DOI:
    10.1016/j.ijrobp.2006.07.118
  • 发表时间:
    2006-11-01
  • 期刊:
  • 影响因子:
  • 作者:
    Janine Erler;Quynh Le;Amato J. Giaccia
  • 通讯作者:
    Amato J. Giaccia
Lysyl oxidase is essential for hypoxia-induced metastasis
赖氨酰氧化酶对于缺氧诱导的转移是必不可少的
  • DOI:
    10.1038/nature04695
  • 发表时间:
    2006-04-27
  • 期刊:
  • 影响因子:
    48.500
  • 作者:
    Janine T. Erler;Kevin L. Bennewith;Monica Nicolau;Nadja Dornhöfer;Christina Kong;Quynh-Thu Le;Jen-Tsan Ashley Chi;Stefanie S. Jeffrey;Amato J. Giaccia
  • 通讯作者:
    Amato J. Giaccia
Hypoxic gene expression and metastasis
  • DOI:
    10.1023/b:canc.0000031768.89246.d7
  • 发表时间:
    2004-08-01
  • 期刊:
  • 影响因子:
    8.700
  • 作者:
    Quynh-Thu Le;Nicholas C. Denko;Amato J. Giaccia
  • 通讯作者:
    Amato J. Giaccia
Therapeutic targeting of the functionally elusive TAM receptor family
对功能上难以捉摸的 TAM 受体家族的治疗靶向
  • DOI:
    10.1038/s41573-023-00846-8
  • 发表时间:
    2023-12-13
  • 期刊:
  • 影响因子:
    101.800
  • 作者:
    Yu Rebecca Miao;Erinn B. Rankin;Amato J. Giaccia
  • 通讯作者:
    Amato J. Giaccia

Amato J. Giaccia的其他文献

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{{ truncateString('Amato J. Giaccia', 18)}}的其他基金

Project 1: Inhibition of Complement C5aR1 Radioprotects Normal Tissue and Radiosensitizes Tumors
项目 1:抑制补体 C5aR1 辐射保护正常组织并使肿瘤辐射增敏
  • 批准号:
    10707880
  • 财政年份:
    2022
  • 资助金额:
    $ 76.29万
  • 项目类别:
Project 1: Inhibition of Complement C5aR1 Radioprotects Normal Tissue and Radiosensitizes Tumors
项目 1:抑制补体 C5aR1 辐射保护正常组织并使肿瘤辐射增敏
  • 批准号:
    10334199
  • 财政年份:
    2022
  • 资助金额:
    $ 76.29万
  • 项目类别:
Preclinical Testing of a Novel Therapy Targeting AXL in Advanced Kidney Cancer
针对晚期肾癌 AXL 的新疗法的临床前测试
  • 批准号:
    8949353
  • 财政年份:
    2016
  • 资助金额:
    $ 76.29万
  • 项目类别:
The Impact of Mitochondrial Repression and Lipid Accumulation by HIF on Tumor Growth
HIF 抑制线粒体和脂质积累对肿瘤生长的影响
  • 批准号:
    10212325
  • 财政年份:
    2015
  • 资助金额:
    $ 76.29万
  • 项目类别:
HIF-1alpha, a Survival and Differentiation Factor for Cartilage
HIF-1alpha,软骨的存活和分化因子
  • 批准号:
    8609400
  • 财政年份:
    2013
  • 资助金额:
    $ 76.29万
  • 项目类别:
Administration & Scientific Support
行政
  • 批准号:
    8208647
  • 财政年份:
    2011
  • 资助金额:
    $ 76.29万
  • 项目类别:
Regulation of Tumor and Metastatic Growth by Hypoxia and CTGF
缺氧和 CTGF 对肿瘤和转移性生长的调节
  • 批准号:
    8492949
  • 财政年份:
    2011
  • 资助金额:
    $ 76.29万
  • 项目类别:
Regulation of Tumor and Metastatic Growth by Hypoxia and CTGF
缺氧和 CTGF 对肿瘤和转移性生长的调节
  • 批准号:
    8208641
  • 财政年份:
    2011
  • 资助金额:
    $ 76.29万
  • 项目类别:
Radiation Biology
放射生物学
  • 批准号:
    8180970
  • 财政年份:
    2010
  • 资助金额:
    $ 76.29万
  • 项目类别:
Postdoctoral Training in the Radiation Sciences
放射科学博士后培训
  • 批准号:
    7233332
  • 财政年份:
    2007
  • 资助金额:
    $ 76.29万
  • 项目类别:

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UMSC-Exo通过调控Ribosome biogenesis诱导心肌再生的策略及机制研究
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