2. Academic Validation
  3. Isocitrate dehydrogenases 2-mediated dysfunctional metabolic reprogramming promotes intestinal cancer progression via regulating HIF-1A signaling pathway

Isocitrate dehydrogenases 2-mediated dysfunctional metabolic reprogramming promotes intestinal cancer progression via regulating HIF-1A signaling pathway

  • Int Immunopharmacol. 2024 Oct 25:140:112828. doi: 10.1016/j.intimp.2024.112828.
Shixiong Liu 1,  Yun Zhou 2,  Yarong Chen 3,  Yuqin Qiao 3,  Lumucao Bai 3,  Shenhua Zhang 4,  Dongfang Men 4,  Haibu Zhang 4,  Fen Pan 4,  Yongshen Gao 4,  Jijing Wang 4,  Yuping Wang 5
Affiliations

Affiliations

  • 1 Department of Geriatrics, The First Hospital of Lanzhou University, Lanzhou 730000, China; Center of Hyperbaric Oxygen Therapy, The First Hospital of Lanzhou University, Lanzhou 730000, China.
  • 2 Department of Geriatrics, The First Hospital of Lanzhou University, Lanzhou 730000, China.
  • 3 The First Clinical Medical College, Lanzhou University, Lanzhou 730000, China.
  • 4 Center of R&D for New Drug Discovery and Innovation, Nanjing BioMed Institute, Nanjing 25000, China.
  • 5 Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou 730000, China. Electronic address: wangyuping@lzu.edu.cn.
PMID: 39094359 DOI: 10.1016/j.intimp.2024.112828
Abstract

Changes in isocitrate dehydrogenases (IDH) lead to the production of the cancer-causing metabolite 2-hydroxyglutarate, making them a cause of Cancer. However, the specific role of IDH in the progression of colon Cancer is still not well understood. Our current study provides evidence that IDH2 is significantly increased in colorectal Cancer (CRC) cells and actively promotes cell growth in vitro and the development of tumors in vivo. Inhibiting the activity of IDH2, either through genetic silencing or pharmacological inhibition, results in a significant increase in α-ketoglutarate (α-KG), indicating a decrease in the reductive citric acid cycle. The excessive accumulation of α-KG caused by the inactivation of IDH2 obstructs the generation of ATP in mitochondria and promotes the downregulation of HIF-1A, eventually inhibiting glycolysis. This dual metabolic impact results in a reduction in ATP levels and the suppression of tumor growth. Our study reveals a metabolic trait of colorectal Cancer cells, which involves the active utilization of glutamine through reductive citric acid cycle metabolism. The data suggests that IDH2 plays a crucial role in this metabolic process and has the potential to be a valuable target for the advancement of treatments for colorectal Cancer.

Keywords

Citric acid cycle; Colorectal cancer; Glycolysis; Isocitrate dehydrogenases; α-ketoglutarate.

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