The regulatory mechanisms and inhibitors of isocitrate dehydrogenase 1 in cancer

Liu, Yang; Xu, Wei; Li, Mingxue; Yang, Yueying; Sun, Dejuan; Chen, Lidian; Li, Hua; Chen, Lixia

doi:10.1016/j.apsb.2022.12.019

Cited by 7 publications

(3 citation statements)

References 185 publications

(269 reference statements)

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“…From a therapeutic perspective, wild-type IDH inhibitors are also of interest to be developed for the treatment of patients with cancer who have high IDH1 WT high expression. Ivosidenib is a small-molecule inhibitor targeting mutant IDH1 approved by the US Food and Drug Administration for the treatment of patients with AML or cholangiocarcinoma ( 65 ). Ivosidenib was reported to act also as an IDH1 WT inhibitor, although a higher inhibitory concentration is needed, or low magnesium condition is required ( 25 , 66 ).…”

Section: Discussionmentioning

confidence: 99%

Wild-type IDH1 maintains NSCLC stemness and chemoresistance through activation of the serine biosynthetic pathway

Zhang,

Yu,

Yang

et al. 2023

Sci. Transl. Med.

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Tumor-initiating cells (TICs) reprogram their metabolic features to meet their bioenergetic, biosynthetic, and redox demands. Our previous study established a role for wild-type isocitrate dehydrogenase 1 (IDH1 WT ) as a potential diagnostic and prognostic biomarker for non–small cell lung cancer (NSCLC), but how IDH1 WT modulates NSCLC progression remains elusive. Here, we report that IDH1 WT activates serine biosynthesis by enhancing the expression of phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1), the first and second enzymes of de novo serine synthetic pathway. Augmented serine synthesis leads to GSH/ROS imbalance and supports pyrimidine biosynthesis, maintaining tumor initiation capacity and enhancing gemcitabine chemoresistance. Mechanistically, we identify that IDH1 WT interacts with and stabilizes PHGDH and fragile X–related protein-1 (FXR1) by impeding their association with the E3 ubiquitin ligase parkin by coimmunoprecipitation assay and proximity ligation assay. Subsequently, stabilized FXR1 supports PSAT1 mRNA stability and translation, as determined by actinomycin D chase experiment and in vitro translation assay. Disrupting IDH1 WT -PHGDH and IDH1 WT -FXR1 interactions synergistically reduces NSCLC stemness and sensitizes NSCLC cells to gemcitabine and serine/glycine–depleted diet therapy in lung cancer xenograft models. Collectively, our findings offer insights into the role of IDH1 WT in serine metabolism, highlighting IDH1 WT as a potential therapeutic target for eradicating TICs and overcoming gemcitabine chemoresistance in NSCLC.

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Section: Discussionmentioning

confidence: 99%

Wild-type IDH1 maintains NSCLC stemness and chemoresistance through activation of the serine biosynthetic pathway

Zhang,

Yu,

Yang

et al. 2023

Sci. Transl. Med.

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“…These mutations disrupt cell metabolism and epigenetic regulation, thereby promoting tumorigenesis. IDH1, in particular, is an important molecular marker in patients with glioma and acute myeloid leukemia [ 10 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Identification of ALDOB as a novel prognostic biomarker in kidney clear cell renal cell carcinoma

Li,

Xu,

et al. 2024

Heliyon

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“…Isocitrate dehydrogenases (IDHs) are members of a class of rate-limiting enzymes in the tricarboxylic acid cycle involved in cellular energy metabolism, catalyzing the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) and CO2, and converts NAD(P)+ into NAD(P)H. Single nucleotide mutations in IDH exons are a frequent molecular parameter in a variety of cancers [ 1 ], with mutations in the R-encoding codon 132 of IDH1 representing the most frequently found alteration [ 2 ]. Mutant IDH proteins possess a neomorphic enzymatic activity, reducing α-KG) to the rare but structurally similar metabolite D-2-hydroxyglutarate (2-HG) [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

The development of a hiPSC-based platform to identify tissue-dependencies of IDH1 R132H

Mehjardi,

Kessler,

Sanin

et al. 2023

Cell Death Discov.

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The application of patient-derived (PD) in vitro tumor models represents the classical strategy for clinical translational oncology research. Using these cellular heterogeneous cultures for the isolation of cancer stem cells (CSCs), suggested to be the main driver for disease malignancy, relies on the use of surrogate biomarkers or is based on CSC-enriching culture conditions. However, the ability of those strategies to exclusively and efficiently enrich for CSC pool has been questioned. Here we present an alternative in vitro CSC model based on the oncogenic transformation of single clone-derived human induced pluripotent stem cells (hiPSC). Hotspot mutations in the DNA encoding for the R132 codon of the enzyme isocitrate dehydrogenase 1 (IDH1) and codon R175 of p53 are commonly occurring molecular features of different tumors and were selected for our transformation strategy. By choosing p53 mutant glial tumors as our model disease, we show that in vitro therapy discovery tests on IDH1-engineered synthetic CSCs (sCSCs) can identify kinases-targeting chemotherapeutics that preferentially target tumor cells expressing corresponding genetic alteration. In contrast, neural stem cells (NSCs) derived from the IDH1R132H overexpressing hiPSCs increase their resistance to the tested interventions indicating glial–to-neural tissue-dependent differences of IDH1R132H. Taken together, we provide proof for the potential of our sCSC technology as a potent addition to biomarker-driven drug development projects or studies on tumor therapy resistance. Moreover, follow-up projects such as comparing in vitro drug sensitivity profiles of hiPSC-derived tissue progenitors of different lineages, might help to understand a variety of tissue-related functions of IDH1 mutations.

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The regulatory mechanisms and inhibitors of isocitrate dehydrogenase 1 in cancer

Cited by 7 publications

References 185 publications

Wild-type IDH1 maintains NSCLC stemness and chemoresistance through activation of the serine biosynthetic pathway

Wild-type IDH1 maintains NSCLC stemness and chemoresistance through activation of the serine biosynthetic pathway

Identification of ALDOB as a novel prognostic biomarker in kidney clear cell renal cell carcinoma

The development of a hiPSC-based platform to identify tissue-dependencies of IDH1 R132H

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