α-KG Inhibits Tumor Growth of Diffuse Large B-cell Lymphoma by Inducing ROS and TP53-mediated Ferroptosis

Overview

Journal Cell Death Discov

Date 2023 Jun 12

PMID 37308557

Authors

Yiqing Cai

Liemei Lv

Tiange Lu

Mengfei Ding

Zhuoya Yu

Xiaomin Chen

Xiangxiang Zhou

Xin Wang

Affiliations

Soon will be listed here.

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.

Citing Articles

αKG-induced oxidative stress and mTOR inhibition as a therapeutic strategy for liver cancer.

Choi S, Kim M, You J Med Oncol. 2025; 42(4):105.

PMID: 40080333 PMC: 11906577. DOI: 10.1007/s12032-025-02653-0.

SH3GL1-activated FTH1 inhibits ferroptosis and confers doxorubicin resistance in diffuse large B-cell lymphoma.

Duan Z, Wang W, Wang Y, Wang R, Hua W, Shang C Clin Transl Med. 2025; 15(3):e70246.

PMID: 40038872 PMC: 11879899. DOI: 10.1002/ctm2.70246.

Amino Acid Metabolism-Related Gene Kynureninase (KYNU) as a Prognostic Predictor and Regulator of Diffuse Large B-Cell Lymphoma.

Zhang Y, Feng S, Lv L, Wang C, Kong R, Zhong G Biochem Genet. 2025; .

PMID: 39932613 DOI: 10.1007/s10528-025-11047-w.

Regulation and therapy: the role of ferroptosis in DLBCL.

Wang Y, He Z, Dong X, Yao Y, Chen Q, Shi Y Front Pharmacol. 2025; 15():1458412.

PMID: 39834804 PMC: 11743434. DOI: 10.3389/fphar.2024.1458412.

Apoliprotein E-mediated ferroptosis controls cellular proliferation in chronic lymphocytic leukemia.

Nardi F, Del Prete R, Drago R, Di Rita A, Vallone F, Ciofini S Leukemia. 2024; 39(1):122-133.

PMID: 39443737 PMC: 11717695. DOI: 10.1038/s41375-024-02442-0.

References

Wu C, Hsieh P, Lee Y, Kuo W, Wu R, Lin Y . Nuclear Respiratory Factor 1 Overexpression Inhibits Proliferation and Migration of PC3 Prostate Cancer Cells. Cancer Genomics Proteomics. 2022; 19(5):614-623. PMC: 9353720. DOI: 10.21873/cgp.20346. View

Zhang J, Zhou B, Sun R, Ai Y, Cheng K, Li F . The metabolite α-KG induces GSDMC-dependent pyroptosis through death receptor 6-activated caspase-8. Cell Res. 2021; 31(9):980-997. PMC: 8410789. DOI: 10.1038/s41422-021-00506-9. View

He J, Chen Z, Xue Q, Sun P, Wang Y, Zhu C . Identification of molecular subtypes and a novel prognostic model of diffuse large B-cell lymphoma based on a metabolism-associated gene signature. J Transl Med. 2022; 20(1):186. PMC: 9036805. DOI: 10.1186/s12967-022-03393-9. View

Davis R, Ngo V, Lenz G, Tolar P, Young R, Romesser P . Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature. 2010; 463(7277):88-92. PMC: 2845535. DOI: 10.1038/nature08638. View

Kodama M, Oshikawa K, Shimizu H, Yoshioka S, Takahashi M, Izumi Y . A shift in glutamine nitrogen metabolism contributes to the malignant progression of cancer. Nat Commun. 2020; 11(1):1320. PMC: 7078194. DOI: 10.1038/s41467-020-15136-9. View

Kang H, Lee J, Oh K, Lee E, Han B, Park K . IDH1-dependent α-KG regulates brown fat differentiation and function by modulating histone methylation. Metabolism. 2020; 105:154173. DOI: 10.1016/j.metabol.2020.154173. View

Huo Y, Xu P, Wang L, Zhong H, Fu D, Shi Q . Dynamic change of soluble interleukin-2 receptor distinguished molecular heterogeneity and microenvironment alterations in diffuse large B-cell lymphoma. Biomark Res. 2022; 10(1):51. PMC: 9316360. DOI: 10.1186/s40364-022-00401-4. View

Atlante S, Visintin A, Marini E, Savoia M, Dianzani C, Giorgis M . α-ketoglutarate dehydrogenase inhibition counteracts breast cancer-associated lung metastasis. Cell Death Dis. 2018; 9(7):756. PMC: 6037705. DOI: 10.1038/s41419-018-0802-8. View

Xie N, Zhang L, Gao W, Huang C, Huber P, Zhou X . NAD metabolism: pathophysiologic mechanisms and therapeutic potential. Signal Transduct Target Ther. 2020; 5(1):227. PMC: 7539288. DOI: 10.1038/s41392-020-00311-7. View

10.

Chen D, Chu B, Yang X, Liu Z, Jin Y, Kon N . iPLA2β-mediated lipid detoxification controls p53-driven ferroptosis independent of GPX4. Nat Commun. 2021; 12(1):3644. PMC: 8206155. DOI: 10.1038/s41467-021-23902-6. View

11.

Zhu L, Zhu X, Wu Y . Effects of Glucose Metabolism, Lipid Metabolism, and Glutamine Metabolism on Tumor Microenvironment and Clinical Implications. Biomolecules. 2022; 12(4). PMC: 9028125. DOI: 10.3390/biom12040580. View

12.

Nuan-Aliman S, Bordereaux D, Thieblemont C, Baud V . The Alternative RelB NF-kB Subunit Exerts a Critical Survival Function upon Metabolic Stress in Diffuse Large B-Cell Lymphoma-Derived Cells. Biomedicines. 2022; 10(2). PMC: 8961793. DOI: 10.3390/biomedicines10020348. View

13.

Shin D, Lee J, You J, Kim D, Roh J . Dihydrolipoamide dehydrogenase regulates cystine deprivation-induced ferroptosis in head and neck cancer. Redox Biol. 2020; 30:101418. PMC: 6957841. DOI: 10.1016/j.redox.2019.101418. View

14.

Schmitt A, Xu W, Bucher P, Grimm M, Konantz M, Horn H . Dimethyl fumarate induces ferroptosis and impairs NF-κB/STAT3 signaling in DLBCL. Blood. 2021; 138(10):871-884. DOI: 10.1182/blood.2020009404. View

15.

Alizadeh A, Eisen M, Davis R, Ma C, Lossos I, Rosenwald A . Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000; 403(6769):503-11. DOI: 10.1038/35000501. View

16.

Zhou Z, Sehn L, Rademaker A, Gordon L, LaCasce A, Crosby-Thompson A . An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era. Blood. 2013; 123(6):837-42. PMC: 5527396. DOI: 10.1182/blood-2013-09-524108. View

17.

La Maestra S, Micale R, Ferretti M, Izzotti A, Gaggero L . Attenuation of oxidative stress and chromosomal aberrations in cultured macrophages and pulmonary cells following self-sustained high temperature synthesis of asbestos. Sci Rep. 2020; 10(1):8581. PMC: 7244567. DOI: 10.1038/s41598-020-65620-x. View

18.

Mestre-Farrera A, Bruch-Oms M, Pena R, Rodriguez-Morato J, Alba-Castellon L, Comerma L . Glutamine-Directed Migration of Cancer-Activated Fibroblasts Facilitates Epithelial Tumor Invasion. Cancer Res. 2020; 81(2):438-451. DOI: 10.1158/0008-5472.CAN-20-0622. View

19.

Burch J, Marcero J, Maschek J, Cox J, Jackson L, Medlock A . Glutamine via α-ketoglutarate dehydrogenase provides succinyl-CoA for heme synthesis during erythropoiesis. Blood. 2018; 132(10):987-998. PMC: 6128084. DOI: 10.1182/blood-2018-01-829036. View

20.

Schmitz R, Wright G, Huang D, Johnson C, Phelan J, Wang J . Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma. N Engl J Med. 2018; 378(15):1396-1407. PMC: 6010183. DOI: 10.1056/NEJMoa1801445. View