Wild-Type IDH Enzymes as Actionable Targets for Cancer Therapy

Bergaggio, Elisa; Piva, Roberto

doi:10.3390/cancers11040563

Cited by 44 publications

(44 citation statements)

References 104 publications

(129 reference statements)

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“…Some cancers, such as glioblastoma, chondrosarcoma, leukemia and colorectal cancer, have mutations in isocitrate dehydrogenase 1/2 (IDH1/2) [13,[39][40][41]. Mutant IDH1/2 uses NADPH to convert α-ketoglutarate (α-KG) into D-2HG, an oncometabolite that causes hypermethylation at…”

Section: Targeting Nad Synthesismentioning

confidence: 99%

“…IDH exists in three isozymes, namely IDH1, IDH2 and IDH3. IDH1, located in the cytosol and peroxisome, is encoded by the IDH1 gene on chromosome 2q34, while IDH2 is localized in the mitochondria and is encoded by the gene located on chromosome 15q26.1 [41]. Both enzymes are NADP-dependent, share high degree of homology and conduct a reversible reaction to maintain the isocitrate pool [12].…”

Section: Mutant Isocitrate Dehydrogenases Inhibit Nad Production In Cmentioning

confidence: 99%

“…Both enzymes are NADP-dependent, share high degree of homology and conduct a reversible reaction to maintain the isocitrate pool [12]. Unlike the other two isozymes, IDH3, localized in the mitochondria, exists as a heterocomplex enzyme consisting of α, β, and γ subunits that are encoded by IDH3A (15q25.1), IDH3B (20p13), and IDH3C (Xq28) genes, respectively [41]. IDH3 is activated by adenosine diphosphate (ADP) and inhibited by adenosine triphosphate (ATP).…”

Section: Mutant Isocitrate Dehydrogenases Inhibit Nad Production In Cmentioning

confidence: 99%

“…IDH3 is activated by adenosine diphosphate (ADP) and inhibited by adenosine triphosphate (ATP). In order to ensure the continuity of TCA cycle, IDH3 conducts the irreversible conversion of isocitrate to maintain the α-KG pool [12,41,81].…”

Section: Mutant Isocitrate Dehydrogenases Inhibit Nad Production In Cmentioning

confidence: 99%

“…Demonstrating the effect of restricting the NAD pool in halting cancer progression requires the inhibition of vital pathways, and the reduction of redundancy [38]. This may be achieved in cancer cells that are deficient in one of the NAD biogenesis pathways.Some cancers, such as glioblastoma, chondrosarcoma, leukemia and colorectal cancer, have mutations in isocitrate dehydrogenase 1/2 (IDH1/2) [13,[39][40][41]. Mutant IDH1/2 uses NADPH to convert α-ketoglutarate (α-KG) into D-2HG, an oncometabolite that causes hypermethylation at…”

mentioning

confidence: 99%

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NAD- and NADPH-Contributing Enzymes as Therapeutic Targets in Cancer: An Overview

et al. 2020

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Actively proliferating cancer cells require sufficient amount of NADH and NADPH for biogenesis and to protect cells from the detrimental effect of reactive oxygen species. As both normal and cancer cells share the same NAD biosynthetic and metabolic pathways, selectively lowering levels of NAD(H) and NADPH would be a promising strategy for cancer treatment. Targeting nicotinamide phosphoribosyltransferase (NAMPT), a rate limiting enzyme of the NAD salvage pathway, affects the NAD and NADPH pool. Similarly, lowering NADPH by mutant isocitrate dehydrogenase 1/2 (IDH1/2) which produces D-2-hydroxyglutarate (D-2HG), an oncometabolite that downregulates nicotinate phosphoribosyltransferase (NAPRT) via hypermethylation on the promoter region, results in epigenetic regulation. NADPH is used to generate D-2HG, and is also needed to protect dihydrofolate reductase, the target for methotrexate, from degradation. NAD and NADPH pools in various cancer types are regulated by several metabolic enzymes, including methylenetetrahydrofolate dehydrogenase, serine hydroxymethyltransferase, and aldehyde dehydrogenase. Thus, targeting NAD and NADPH synthesis under special circumstances is a novel approach to treat some cancers. This article provides the rationale for targeting the key enzymes that maintain the NAD/NADPH pool, and reviews preclinical studies of targeting these enzymes in cancers.

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Section: Targeting Nad Synthesismentioning

confidence: 99%

Section: Mutant Isocitrate Dehydrogenases Inhibit Nad Production In Cmentioning

confidence: 99%

Section: Mutant Isocitrate Dehydrogenases Inhibit Nad Production In Cmentioning

confidence: 99%

Section: Mutant Isocitrate Dehydrogenases Inhibit Nad Production In Cmentioning

confidence: 99%

mentioning

confidence: 99%

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NAD- and NADPH-Contributing Enzymes as Therapeutic Targets in Cancer: An Overview

et al. 2020

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Phosphorylation of IDH1 Facilitates Progestin Resistance in Endometrial Cancer

Li,

Qin,

et al. 2024

Advanced Science

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The progestin regimen is one of the main therapeutic strategies for women with endometrial cancer who undergo conservative management. Although many patients respond well to initial therapy, progestin‐refractory disease inevitably emerges, and the molecular basis underlying progestin resistance has not been comprehensively elucidated. Herein, they demonstrated progestin results in p38‐dependent IDH1 Thr 77 phosphorylation (pT77‐IDH1). pT77‐IDH1 translocates into the nucleus and is recruited to chromatin through its interaction with OCT6. IDH1‐produced α‐ketoglutarate (αKG) then facilitates the activity of OCT6 to promote focal adhesion related target gene transcription to confer progestin resistance. Pharmacological inhibition of p38 or focal adhesion signaling sensitizes endometrial cancer cells to progestin in vivo. The study reveals p38‐dependent pT77‐IDH1 as a key mediator of progestin resistance and a promising target for improving the efficacy of progestin therapy.

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The prognostic significance of wild-type isocitrate dehydrogenase 2 (IDH2) in breast cancer

Aljohani

Toss

Kurozumi

et al. 2019

Breast Cancer Res Treat

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Background Lymphovascular invasion (LVI) is a prerequisite step in breast cancer (BC) metastasis. We have previously identified wild-type isocitrate dehydrogenase 2 (IDH2) as a key putative driver of LVI. Thus, we explored the prognostic significance of IDH2 at transcriptome and protein expression levels in pre-invasive and invasive disease. Methods Utlising tissue microarrays from a large well annotated BC cohort including ductal carcinoma in situ and invasive breast cancer (IBC), IDH2 was assessed at the transcriptomic and proteomic level. The associations between clinicopathological factors including LVI status, prognosis and the expression of IDH2 were evaluated. Results In pure DCIS and IBC, high IDH2 protein expression was associated with features of aggressiveness including high nuclear grade, larger size, comedo necrosis and hormonal receptor negativity and LVI, higher grade, larger tumour size, high NPI, HER2 positivity, and hormonal receptor negativity, respectively. High expression of IDH2 either in mRNA or in protein levels was associated with poor patient’s outcome in both DCIS and IBC. Multivariate analysis revealed that IDH2 protein expression was an independent risk factor for shorter BC specific-survival. Conclusion Further functional studies to decipher the role of IDH2 and its mechanism of action as a driver of BC progression and LVI are warranted.

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Wild-Type IDH Enzymes as Actionable Targets for Cancer Therapy

Cited by 44 publications

References 104 publications

NAD- and NADPH-Contributing Enzymes as Therapeutic Targets in Cancer: An Overview

NAD- and NADPH-Contributing Enzymes as Therapeutic Targets in Cancer: An Overview

Phosphorylation of IDH1 Facilitates Progestin Resistance in Endometrial Cancer

The prognostic significance of wild-type isocitrate dehydrogenase 2 (IDH2) in breast cancer

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