The Role of Mortalin in Thyroid Cancer

Mortalin 在甲状腺癌中的作用

基本信息

  • 批准号:
    10583210
  • 负责人:
  • 金额:
    $ 43.63万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-07-10 至 2028-06-30
  • 项目状态:
    未结题

项目摘要

The goal of this project is to elucidate the mechanism by which mortalin is upregulated in thyroid cancer, determine the role of mortalin for tumor cell metabolism, and evaluate the potential of the metabolic processes that mortalin regulates as a therapeutic target. Metabolic reprogramming in the processes of energy and building block production is critical for tumor development and maintenance, but is associated with the risk of a lethal metabolic stress. It is therefore conceivable that malignant tumor cells might have successfully developed a protective mechanism in this context. If identified, such a mechanism may be targeted to unleash a death signal in tumor cells. We previously demonstrated that depletion of mortalin (GRP75/HSPA9), a molecular chaperone in the HSP70 family, causes lethal bioenergetic and oxidative stress in tumor cells, proposing that mortalin upregulation is a mechanism to protect tumor cells from a metabolic stress. Current understanding of the role of mortalin and its regulation is very limited in thyroid cancer, which is a metabolically active tumor. Our analysis of the TCGA RNAseq dataset revealed that a thyroid cancer-specific correlation exists between mortalin and ESRRA, an orphan transcription factor that regulates metabolic reprogramming. In our preliminary study, ESRRA depletion downregulated mortalin expression and induced cell death in different thyroid tumor cell lines, while this lethality was substantially abrogated by mortalin overexpression. These data led us to hypothesize that ESRRA is a tumor type- specific transcription factor that mediates mortalin overexpression in thyroid cancer and that mortalin is necessary for ESRRA to regulate thyroid tumor cell metabolism. Our metabolome analysis suggests that mortalin knockdown markedly depletes acetyl-CoA and its precursors in the context of the reductive TCA cycle, while increasing lactate and glucose. Moreover, depletion of ATP-citrate lyase (ACL), the enzyme that synthesizes cytosolic acetyl-CoA from citrate produced through the reductive TCA cycle, induced similar lethal effects as mortalin depletion whereas overexpression of pyruvate kinase M2 (PKM2), the enzyme that produces pyruvate to often facilitate the Warburg effect, conferred tolerance to mortalin depletion. Based upon these data, we further hypothesize that mortalin regulates the interplay between the Warburg effect and the reductive TCA cycle to facilitate cytosolic acetyl-CoA production. By extension, we predict that ACL inhibition is a promising strategy to suppress mortalin-dependent thyroid tumor cells and can be effectively combined with glycolysis inhibition. To test these hypotheses, Aim 1 will determine how ESRRA regulates mortalin transcription and examine their correlated expression and functional relationship in different thyroid tumor subtypes. Aim 2 will determine how mortalin regulates the interplay between glycolysis and the reductive TCA cycle to facilitate cytosolic acetyl-CoA production. Aim 3 will determine whether ACL is an effective target to suppress mortalin-dependent thyroid tumor cells in vitro and in vivo.
这个项目的目标是阐明死亡素在甲状腺癌中上调的机制,

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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Jong-In Park其他文献

Jong-In Park的其他文献

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{{ truncateString('Jong-In Park', 18)}}的其他基金

Mechanisms of MEK/ERK growth arrest signaling
MEK/ERK 生长抑制信号传导机制
  • 批准号:
    8460092
  • 财政年份:
    2010
  • 资助金额:
    $ 43.63万
  • 项目类别:
Mechanisms of MEK/ERK growth arrest signaling
MEK/ERK 生长抑制信号传导机制
  • 批准号:
    7983416
  • 财政年份:
    2010
  • 资助金额:
    $ 43.63万
  • 项目类别:
Mechanisms of MEK/ERK growth arrest signaling
MEK/ERK 生长抑制信号传导机制
  • 批准号:
    8257495
  • 财政年份:
    2010
  • 资助金额:
    $ 43.63万
  • 项目类别:
Mechanisms of MEK/ERK growth arrest signaling
MEK/ERK 生长抑制信号传导机制
  • 批准号:
    9174948
  • 财政年份:
    2010
  • 资助金额:
    $ 43.63万
  • 项目类别:
Mechanisms of MEK/ERK growth arrest signaling
MEK/ERK 生长抑制信号传导机制
  • 批准号:
    9759770
  • 财政年份:
    2010
  • 资助金额:
    $ 43.63万
  • 项目类别:
Mechanisms of MEK/ERK growth arrest signaling
MEK/ERK 生长抑制信号传导机制
  • 批准号:
    8090466
  • 财政年份:
    2010
  • 资助金额:
    $ 43.63万
  • 项目类别:

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