1. Academic Validation
  2. α-KG inhibits tumor growth of diffuse large B-cell lymphoma by inducing ROS and TP53-mediated ferroptosis

α-KG inhibits tumor growth of diffuse large B-cell lymphoma by inducing ROS and TP53-mediated ferroptosis

  • Cell Death Discov. 2023 Jun 12;9(1):182. doi: 10.1038/s41420-023-01475-1.
Yiqing Cai 1 Liemei Lv 1 Tiange Lu 1 Mengfei Ding 1 Zhuoya Yu 1 Xiaomin Chen 1 Xiangxiang Zhou 2 3 4 5 Xin Wang 6 7 8 9 10
Affiliations

Affiliations

  • 1 Department of Hematology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China.
  • 2 Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China. xiangxiangzhou@sdu.edu.cn.
  • 3 Shandong Provincial Engineering Research Center of Lymphoma, Jinan, Shandong, 250021, China. xiangxiangzhou@sdu.edu.cn.
  • 4 Branch of National Clinical Research Center for Hematologic Diseases, Jinan, Shandong, 250021, China. xiangxiangzhou@sdu.edu.cn.
  • 5 National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou, 251006, China. xiangxiangzhou@sdu.edu.cn.
  • 6 Department of Hematology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China. xinw007@126.com.
  • 7 Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China. xinw007@126.com.
  • 8 Shandong Provincial Engineering Research Center of Lymphoma, Jinan, Shandong, 250021, China. xinw007@126.com.
  • 9 Branch of National Clinical Research Center for Hematologic Diseases, Jinan, Shandong, 250021, China. xinw007@126.com.
  • 10 National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou, 251006, China. xinw007@126.com.
Abstract

Metabolic reprogramming is a hallmark of human malignancies. Dysregulation of glutamine metabolism is essential for tumorigenesis, microenvironment remodeling, and therapeutic resistance. Based on the untargeted metabolomics Sequencing, we identified that the glutamine metabolic pathway was up-regulated in the serum of patients with primary DLBCL. High levels of glutamine were associated with inferior clinical outcomes, indicative of the prognostic value of glutamine in DLBCL. In contrast, the derivate of glutamine alpha-ketoglutarate (α-KG) was negatively correlated with the invasiveness features of DLBCL patients. Further, we found that treatment with the cell-permeable derivative of α-KG, known as DM-αKG, significantly suppressed tumor growth by inducing Apoptosis and non-apoptotic cell death. Accumulation of a-KG promoted oxidative stress in double-hit lymphoma (DHL), which depended on malate dehydrogenase 1 (MDH1)-mediated 2-hydroxyglutarate (2-HG) conversion. High levels of Reactive Oxygen Species (ROS) contributed to Ferroptosis induction by promoting lipid peroxidation and TP53 activation. In particular, TP53 overexpression derived from oxidative DNA damage, further leading to the activation of ferroptosis-related pathways. Our study demonstrated the importance of glutamine metabolism in DLBCL progression and highlighted the potential application of α-KG as a novel therapeutic strategy for DHL patients.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-147791
    98.39%, MDH1抑制剂