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IDH2 stabilizes HIF-1α-induced metabolic reprogramming and promotes chemoresistance in urothelial cancer.

Shigeta K, Hasegawa M, Hishiki T, Naito Y, Baba Y, Mikami S, Matsumoto K, Mizuno R, Miyajima A, Kikuchi E
EMBO J 2023
Open on PubMed

1. EMBO J. 2023 Feb 15;42(4):e110620. doi: 10.15252/embj.2022110620. Epub 2023 Jan 13. IDH2 stabilizes HIF-1α-induced metabolic reprogramming and promotes chemoresistance in urothelial cancer. Shigeta K(1), Hasegawa M(2), Hishiki T(3)(4), Naito Y(3), Baba Y(1), Mikami S(5), Matsumoto K(1), Mizuno R(1), Miyajima A(2), Kikuchi E(1)(6), Saya H(3)(7), Kosaka T(1), Oya M(1). Author information: (1)Department of Urology, Keio University School of Medicine, Tokyo, Japan. (2)Department of Urology, Tokai University School of Medicine, Tokyo, Japan. (3)Department of Clinical and Translational Research center, Keio University School of Medicine, Tokyo, Japan. (4)Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan. (5)Division of Pathology, Keio University School of Medicine, Tokyo, Japan. (6)Department of Urology, St. Marianna University School of Medicine, Kanagawa, Japan. (7)Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan. Drug resistance contributes to poor therapeutic response in urothelial carcinoma (UC). Metabolomic analysis suggested metabolic reprogramming in gemcitabine-resistant urothelial carcinoma cells, whereby increased aerobic glycolysis and metabolic stimulation of the pentose phosphate pathway (PPP) promoted pyrimidine biosynthesis to increase the production of the gemcitabine competitor deoxycytidine triphosphate (dCTP) that diminishes its therapeutic effect. Furthermore, we observed that gain-of-function of isocitrate dehydrogenase 2 (IDH2) induced reductive glutamine metabolism to stabilize Hif-1α expression and consequently stimulate aerobic glycolysis and PPP bypass in gemcitabine-resistant UC cells. Interestingly, IDH2-mediated metabolic reprogramming also caused cross resistance to CDDP, by elevating the antioxidant defense via increased NADPH and glutathione production. Downregulation or pharmacological suppression of IDH2 restored chemosensitivity. Since the expression of key metabolic enzymes, such as TIGAR, TKT, and CTPS1, were affected by IDH2-mediated metabolic reprogramming and related to poor prognosis in patients, IDH2 might become a new therapeutic target for restoring chemosensitivity in chemo-resistant urothelial carcinoma. © 2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license. DOI: 10.15252/embj.2022110620 PMCID: PMC9929641 PMID: 36637036 [Indexed for MEDLINE]

15 Figures Extracted
Figure 1
Figure 1 PMC
Metabolic differences among WT, CR, and GR UC cells T24 and UMUC3 cisplatin‐resistant (CR) and gemcitabine‐resistant (GR) urothelial cancer (UC) cel...
Figure 2
Figure 2 PMC
GR cells increases pyrimidine biosynthesis to generate dCTP Schematic of altered mechanisms in GR cells in glycolysis and the pentose phosphate path...
Figure EV1
Figure EV1 PMC
Stimulation of PPP is responsible for chemoresistance in GR cells Relative mRNA expression levels of DHODH, UMPS, CTPS1, CTPS2, TYMS, IMPDH1, ADSL, ...
Figure 3
Figure 3 PMC
Reductive carboxylation produces 2‐HG to stabilize Hif‐1α Levels of intermediate metabolites of the tricarboxylic acid cycle (TCA) cycle in GR cells...
Figure EV2
Figure EV2 PMC
Whole‐exome sequencing analysis of DNA in UC cell lines Details of the whole‐exome sequencing analysis of DNA in T24WT, T24GR, UMUC3WT, and UMUC3GR ...
Figure 4
Figure 4 PMC
Downregulation of HIF1A and IDH2 Relative mRNA expression levels of HIF1A, GLUT1, G6PD, TIGAR, TKT, CTPS1, PKM2, and LDHA in cells transfected with ...
Figure EV3
Figure EV3 PMC
IDH2 down regulation suppresses metabolic rewiring The entire heat map showing intracellular levels of metabolites in T24GR cells transfected with N...
Figure 5
Figure 5 PMC
IDH2 overexpression recapitulate metabolic rewiring Relative mRNA expression levels of IDH2, EGLN1, Hif‐1α, G6PD, TIGAR, TKT, and CTPS1 between J82 ...
Figure 6
Figure 6 PMC
Increased intracellular NADPH levels leads to cross resistance to CDDP Changes in cytotoxicity between WT and GR T24 and UMUC3 cells exposed to incr...
Figure EV4
Figure EV4 PMC
Suppression of oxidative PPP lowers NADPH level Simple schematic of the glycolytic pathway and the pentose phosphate pathway (PPP). The G6PD inhibit...
Figure 7
Figure 7 PMC
AGI6780 restores chemosensitivity in chemo‐resistant UC cells Graph showing the viability of GR cells exposed to various concentrations of GEM for 4...
Figure 8
Figure 8 PMC
High IDH2 expressed patients follow poor prognosis Representative immunostaining of IDH2, CAIX (surrogate marker of Hif‐1α), TIGAR, TKT, and CTPS1 i...
Figure 9
Figure 9 PMC
Mechanism of metabolic reprogramming Graphical summary of the metabolic basis of GEM resistance in UC cells. GR cells demonstrate 2‐HG production by r...
Figure EV5
Figure EV5 PMC
AGI6780 suppresses the entire metabolic reprogramming The viability of J82WT and J82‐IDH2ox cells was assessed by WST assays under treatment with GE...
Figure 15 PMC
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