Attenuated mitochondrial NADP+-dependent isocitrate dehydrogenase activity enhances EGCG-induced apoptosis

Kil, In Sup; Jung, Kyu Ho; Nam, Woo Suk; Park, Jeen‐Woo

doi:10.1016/j.biochi.2011.06.025

Cited by 13 publications

(9 citation statements)

References 47 publications

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“…Our results are in agreement with the data published by the group of Park, showing an increased sensitivity to radiation in different cell types when IDH1 or IDH2 is silenced. 22 , 23 , 24 , 25 However, other studies show increased cell sensitivity to cell death when mutant IDH is overexpressed, in particular in ROS-mediated cell death such as radiation- 26 or BCNU-induced cell death. 27 However, these cells are addicted to glutaminolysis contrary to the glioma cell lines used in our study.…”

Section: Discussionmentioning

confidence: 99%

D-2-Hydroxyglutarate does not mimic all the IDH mutation effects, in particular the reduced etoposide-triggered apoptosis mediated by an alteration in mitochondrial NADH

et al. 2015

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Somatic mutations in isocitrate dehydrogenase (IDH)-1 and -2 have recently been described in glioma. This mutation leads to a neomorphic enzymatic activity as the conversion of isocitrate to alpha ketoglutarate (αKG) is replaced by the conversion of αKG to D-2-hydroxyglutarate (D-2HG) with NADPH oxidation. It has been suggested that this oncometabolite D-2HG via inhibition of αKG-dioxygenases is involved in multiple functions such as epigenetic modifications or hypoxia responses. The present study is aimed at deciphering how the mutant IDH can affect cancer pathogenesis, in particular with respect to its associated oncometabolite D-2HG. We show that the overexpression of mutant IDH in glioma cells or treatment with D-2HG triggered an increase in cell proliferation. However, although mutant IDH reduced cell sensitivity to the apoptotic inducer etoposide, D-2HG exhibited no effect on apoptosis. Instead, we found that the apoptotic effect was mediated through the mitochondrial NADH pool reduction and could be inhibited by oxamate. These data show that besides D-2HG production, mutant IDH affects other crucial metabolite pools. These observations lead to a better understanding of the biology of IDH mutations in gliomas and their response to therapy.

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Section: Discussionmentioning

confidence: 99%

D-2-Hydroxyglutarate does not mimic all the IDH mutation effects, in particular the reduced etoposide-triggered apoptosis mediated by an alteration in mitochondrial NADH

et al. 2015

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“…Furthermore, glutathionylation of isocitrate dehydrogenase inactivates the enzyme [115]; and knockdown of isocitrate dehydrogenase expression by siRNA increases susceptibility to apoptotic stimuli [133]. More recently, it has been reported that enzymatic inactivation of isocitrate dehydrogenase exacerbates (−)-epigallocatechin-3-gallate induced apoptosis in HeLa cells [134]. Thus, the enzymatic activity of isocitrate dehydrogenase appears to play an important role in regulating cell survival.…”

Section: Impairment Of Glutathione Homeostasis In Neurodegeneratimentioning

confidence: 99%

Dysregulation of Glutathione Homeostasis in Neurodegenerative Diseases

2012

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Dysregulation of glutathione homeostasis and alterations in glutathione-dependent enzyme activities are increasingly implicated in the induction and progression of neurodegenerative diseases, including Alzheimer’s, Parkinson’s and Huntington’s diseases, amyotrophic lateral sclerosis, and Friedreich’s ataxia. In this review background is provided on the steady-state synthesis, regulation, and transport of glutathione, with primary focus on the brain. A brief overview is presented on the distinct but vital roles of glutathione in cellular maintenance and survival, and on the functions of key glutathione-dependent enzymes. Major contributors to initiation and progression of neurodegenerative diseases are considered, including oxidative stress, protein misfolding, and protein aggregation. In each case examples of key regulatory mechanisms are identified that are sensitive to changes in glutathione redox status and/or in the activities of glutathione-dependent enzymes. Mechanisms of dysregulation of glutathione and/or glutathione-dependent enzymes are discussed that are implicated in pathogenesis of each neurodegenerative disease. Limitations in information or interpretation are identified, and possible avenues for further research are described with an aim to elucidating novel targets for therapeutic interventions. The pros and cons of administration of N-acetylcysteine or glutathione as therapeutic agents for neurodegenerative diseases, as well as the potential utility of serum glutathione as a biomarker, are critically evaluated.

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“…16 HL-60 cells were incubated in culture medium supplemented with 10 mM dihydrorhodamine 123 (DHR 123) for 20 min, and then washed 3 times with ice-cold PBS. The cells were imaged for FITC fluorescence intensity on an inverted microscope.…”

Section: Measurement Of Mitochondrial Rosmentioning

confidence: 99%

Decursinol angelate inhibits PGE₂-induced survival of the human leukemia HL-60 cell line via regulation of the EP2 receptor and NFκB pathway

Shehzad

Islam

Ahn

et al. 2016

Cancer Biology & Therapy

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Decursinol angelate (DA), an active pyranocoumarin compound from the roots of Angelica gigas, has been reported to possess anti-inflammatory and anti-cancer activities. In a previous study, we demonstrated that prostaglandin E 2 (PGE 2 ) plays a survival role in HL-60 cells by protecting them from the induction of apoptosis via oxidative stress. Flow cytometry and Hoechst staining revealed that PGE 2 suppresses menadione-induced apoptosis, cell shrinkage, and chromatin condensation, by blocking the generation of reactive oxygen species. Treatment of DA was found to reverse the survival effect of PGE 2 as well as restoring the menadione-mediated cleavage of caspase-3, lamin B, and PARP. DA blocked PGE 2 -induced activation of the EP2 receptor signaling pathway, including the activation of PKA and the phosphorylation of CREB. DA also inhibited PGE 2 -induced expression of cyclooxygenase-2 and the activation of the Ras/Raf/ Erk pathway, which activates downstream targets for cell survival. Finally, DA greatly reduced the PGE 2 -induced activation of NF-kB p50 and p65 subunits. These results elucidate a novel mechanism for the regulation of cell survival and apoptosis, and open a gateway for further development and combinatory treatments that can inhibit PGE 2 in cancer cells.

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Attenuated mitochondrial NADP+-dependent isocitrate dehydrogenase activity enhances EGCG-induced apoptosis

Cited by 13 publications

References 47 publications

D-2-Hydroxyglutarate does not mimic all the IDH mutation effects, in particular the reduced etoposide-triggered apoptosis mediated by an alteration in mitochondrial NADH

D-2-Hydroxyglutarate does not mimic all the IDH mutation effects, in particular the reduced etoposide-triggered apoptosis mediated by an alteration in mitochondrial NADH

Dysregulation of Glutathione Homeostasis in Neurodegenerative Diseases

Decursinol angelate inhibits PGE₂-induced survival of the human leukemia HL-60 cell line via regulation of the EP2 receptor and NFκB pathway

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Attenuated mitochondrial NADP+-dependent isocitrate dehydrogenase activity enhances EGCG-induced apoptosis

Cited by 13 publications

References 47 publications

D-2-Hydroxyglutarate does not mimic all the IDH mutation effects, in particular the reduced etoposide-triggered apoptosis mediated by an alteration in mitochondrial NADH

D-2-Hydroxyglutarate does not mimic all the IDH mutation effects, in particular the reduced etoposide-triggered apoptosis mediated by an alteration in mitochondrial NADH

Dysregulation of Glutathione Homeostasis in Neurodegenerative Diseases

Decursinol angelate inhibits PGE2-induced survival of the human leukemia HL-60 cell line via regulation of the EP2 receptor and NFκB pathway

Contact Info

Product

Resources

About

Decursinol angelate inhibits PGE₂-induced survival of the human leukemia HL-60 cell line via regulation of the EP2 receptor and NFκB pathway