Molecular Mechanisms of Fructose-induced Colorectal Cancer Cell Survival

果糖诱导结直肠癌细胞存活的分子机制

基本信息

项目摘要

Project Summary Clear associations have been established between the food we eat and the development and progression of colorectal cancer (CRC). For example, the consumption of fructose increases the risk for CRC development and CRC-specific mortality. However, the mechanism underlying this association is unknown. We have shown that moderate daily exposure to oral high fructose corn syrup (HFCS, a mix of fructose and glucose) leads to larger and more aggressive intestinal adenomas in mice. These effects were absent in mice with genetic deficiency of ketohexokinase (KHK), the enzyme that converts fructose to fructose 1-phosphate (F1P). A metabolomic analysis of these tumors showed that F1P is highly abundant following HFCS exposure, and this increase correlates with a reduction in pyruvate kinase (PK) activity. Therefore, we hypothesize that F1P, the product of KHK, enhances tumor growth by acting as an allosteric inhibitor of PK to promote anabolic metabolism and cell survival. We will test this hypothesis using mouse physiology and organ metabolism, cell and human organoid culture, and recombinant protein biochemistry. In Aim 1, we will genetically and pharmacologically manipulate the M2 isozyme of PK (PKM2) in mice to interrogate its role as a mediator of HFCS-induced tumor growth. In Aim 2, we will define the mechanistic linkage between fructose exposure and cancer cell survival. We have found that cells in culture do not grow faster when exposed to fructose, however we observed a significant improvement in cell viability, especially under conditions of high cell density and hypoxia with fructose in the media. Therefore, we hypothesize that F1P inhibits PKM2 to promote hypoxic cell survival. We will test this hypothesis using cell and organoid culture models exposed to fructose and hypoxia. We will genetically and pharmacologically manipulate KHK and PKM2 expression and activity in these models to determine the specific effects of these proteins on cell metabolism and survival. In Aim 3, we will assess the effects of F1P on recombinant PK isoforms with a particular focus on PKM2. We hypothesize that fructose- derived F1P binds to and inhibits PKM2. We will perform biochemical activity and structural assays to determine the kinetic parameters and oligomeric state of PK isoforms in the presence of F1P. These experiments will reveal the molecular mechanisms of how F1P binds and inhibits PKM2. Together, these aims will change our fundamental understanding of how fructose alters tumor cell metabolism, define the fructose/F1P/PKM2 axis as a metabolic vulnerability of CRC, and provide pre-clinical evidence for PKM2 activators as a novel therapeutic modality to combat CRC.
项目总结

项目成果

期刊论文数量(0)
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Marcus DaSilva Goncalves其他文献

AMPK as a mediator of tissue preservation: time for a shift in dogma?
AMPK 作为组织保存的介质:是时候改变教条了吗?
  • DOI:
    10.1038/s41574-024-00992-y
  • 发表时间:
    2024-05-17
  • 期刊:
  • 影响因子:
    40.000
  • 作者:
    Henning Tim Langer;Maria Rohm;Marcus DaSilva Goncalves;Lykke Sylow
  • 通讯作者:
    Lykke Sylow

Marcus DaSilva Goncalves的其他文献

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{{ truncateString('Marcus DaSilva Goncalves', 18)}}的其他基金

Combination Therapies Targeting Insulin Signaling in Endometrial Cancer
子宫内膜癌中针对胰岛素信号传导的联合疗法
  • 批准号:
    10637167
  • 财政年份:
    2023
  • 资助金额:
    $ 56.36万
  • 项目类别:
Molecular Mechanisms of Fructose-induced Colorectal Cancer Cell Survival
果糖诱导结直肠癌细胞存活的分子机制
  • 批准号:
    10548829
  • 财政年份:
    2022
  • 资助金额:
    $ 56.36万
  • 项目类别:
CANCAN ? CORNELL
可以可以 ?
  • 批准号:
    10625683
  • 财政年份:
    2022
  • 资助金额:
    $ 56.36万
  • 项目类别:
CANCAN ? CORNELL
可以可以 ?
  • 批准号:
    10845767
  • 财政年份:
    2022
  • 资助金额:
    $ 56.36万
  • 项目类别:
The role of PKM2 in dietary lipid absorption and fructose-induced obesity
PKM2 在膳食脂质吸收和果​​糖诱导的肥胖中的作用
  • 批准号:
    10612965
  • 财政年份:
    2022
  • 资助金额:
    $ 56.36万
  • 项目类别:
The Role of Hypoketonemia in the Cancer Anorexia-Cachexia Syndrome
低酮血症在癌症厌食恶病质综合征中的作用
  • 批准号:
    10222611
  • 财政年份:
    2018
  • 资助金额:
    $ 56.36万
  • 项目类别:

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