scholarly journals The Role of Mitochondrial NADPH-Dependent Isocitrate Dehydrogenase in Cancer Cells

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Katarína Smolková ◽  
Petr Ježek
Keyword(s):  
Cancer Cells ◽  
Isocitrate Dehydrogenase ◽  
Competitive Inhibition ◽  
Malignant Tumors ◽  
Krebs Cycle ◽  
Protective Function ◽  
Genome Wide ◽  
Isocitrate Dehydrogenase 2 ◽  
Reductive Carboxylation

Isocitrate dehydrogenase 2 (IDH2) is located in the mitochondrial matrix. IDH2 acts in the forward Krebs cycle as an NADP+-consuming enzyme, providing NADPH for maintenance of the reduced glutathione and peroxiredoxin systems and for self-maintenance by reactivation of cystine-inactivated IDH2 by glutaredoxin 2. In highly respiring cells, the resulting NAD+accumulation then induces sirtuin-3-mediated activating IDH2 deacetylation, thus increasing its protective function. Reductive carboxylation of 2-oxoglutarate by IDH2 (in the reverse Krebs cycle direction), which consumes NADPH, may follow glutaminolysis of glutamine to 2-oxoglutarate in cancer cells. When the reverse aconitase reaction and citrate efflux are added, this overall “anoxic” glutaminolysis mode may help highly malignant tumors survive aglycemia during hypoxia. Intermittent glycolysis would hypothetically be required to provide ATP. When oxidative phosphorylation is dormant, this mode causes substantial oxidative stress. Arg172 mutants of human IDH2—frequently found with similar mutants of cytosolic IDH1 in grade 2 and 3 gliomas, secondary glioblastomas, and acute myeloid leukemia—catalyze reductive carboxylation of 2-oxoglutarate and reduction toD-2-hydroxyglutarate, which strengthens the neoplastic phenotype by competitive inhibition of histone demethylation and 5-methylcytosine hydroxylation, leading to genome-wide histone and DNA methylation alternations.D-2-hydroxyglutarate also interferes with proline hydroxylation and thus may stabilize hypoxia-induced factorα.

scholarly journals 2-hydroxyglutarate inhibits MyoD-mediated differentiation by preventing H3K9 demethylation

2019 ◽  
Vol 116 (26) ◽  
pp. 12851-12856 ◽  
Author(s):  
Juan-Manuel Schvartzman ◽  
Vincent P. Reuter ◽  
Richard P. Koche ◽  
Craig B. Thompson
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Cancer Cells ◽  
Competitive Inhibition ◽  
Mesenchymal Cells ◽  
Genome Wide ◽  
Idh Mutations ◽  
Differentiation Block

Oncogenic IDH1/2 mutations produce 2-hydroxyglutarate (2HG), resulting in competitive inhibition of DNA and protein demethylation. IDH-mutant cancer cells show an inability to differentiate but whether 2HG accumulation is sufficient to perturb differentiation directed by lineage-specifying transcription factors is unknown. A MyoD-driven model was used to study the role of IDH mutations in the differentiation of mesenchymal cells. The presence of 2HG produced by oncogenic IDH2 blocks the ability of MyoD to drive differentiation into myotubes. DNA 5mC hypermethylation is dispensable while H3K9 hypermethylation is required for this differentiation block. IDH2-R172K mutation results in H3K9 hypermethylation and impaired accessibility at myogenic chromatin regions but does not result in genome-wide decrease in accessibility. The results demonstrate the ability of the oncometabolite 2HG to block transcription factor-mediated differentiation in a molecularly defined system.

Complement Component 3 (C3) Is a Mediator of Epithelial-Mesenchymal Transition (EMT)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1421-1421
Author(s):  
Min Soon Cho ◽  
Qianghua Hu ◽  
Rajesha Rupaimoole ◽  
Anil Sood ◽  
Vahid Afshar-Kharghan
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Malignant Tumors ◽  
Mouse Embryos ◽  
Ovarian Cancer Cells ◽  
Mesenchymal Transition ◽  
E Cadherin

Abstract We have shown that complement component 3 (C3) is expressed in malignant ovarian epithelial cells and enhances cell proliferation in vitro and tumor growth in vivo. C3 is secreted by cancer cells into the tumor microenvironment and promotes tumor growth through an autocrine loop. To understand the mechanism of upregulation of C3 expression in malignant epithelial cells, we studied the transcriptional regulation of C3, and found that TWIST1, a major regulator of EMT, binds to the C3 promoter and regulates C3 transcription. Knockdown of the TWIST1 gene reduced C3 mRNA, and TWIST1 overexpression increased C3 mRNA. TWIST1 promotes epithelial-mesenchymal transition (EMT) during normal development and in metastasis of malignant tumors. An important marker of EMT is a reduction in the surface expression of E-cadherin on cells facilitating migration and invasion of these cells. TWIST1 is a transcriptional repressor of E-cadherin; and because TWIST1 increases C3 expression, we investigated whether C3 is also a negative regulator of E-cadherin expression. We overexpressed C3 in ovarian cancer cells by stable transduction of lentivirus carrying C3 cDNA. Overexpression of C3 was associated with 32% reduction in the expression of E-cadherin resulting in enhanced migration ability of cells by 2.3 folds and invasiveness by 1.75 folds, as compared to control cells transduced with control lentivirus. To investigate whether TWIST1-induced reduction in E-cadherin is C3-mediated or not, we studied the effect of TWIST1 overexpression simultaneous with C3 knockdown in ovarian cancer cells. Overexpression of TWIST1 alone resulted in 70% reduction in E-cadherin mRNA and this was completely reversed after simultaneous C3 knockdown in these cells. To investigate the correlation between C3 and TWIST1 in vivo, we studied the co-expression of these two proteins in mouse embryos (physiologic EMT) and in malignant tumors (pathologic EMT). Given the role of EMT in embryogenesis we immunostained mouse embryos at different stages of development, using antibodies against TWIST1 or C3. Transverse section of 9.5-day post-coitum (9.5dpc) mouse embryos showed co-expression of TWIST1 and C3 in otocyst (ot) and hindbrain (hb) of neural crest. In the whole-mounted 11.5dpc mouse embryos, C3 and TWIST1 were co-expressed in limb buds. Given the role of EMT in malignancy, tumors induced in mice after intraperitoneal injection of murine ovarian cancer cells were resected and immunostained for C3 and TWIST1 proteins. TWIST1 and C3 co-localized at tumor edges, where EMT and tumor cells migration occur. Taken together, these data provide evidence that TWIST1 regulates C3 expression, and C3 promotes EMT through E-cadherin. Disclosures No relevant conflicts of interest to declare.

Isocitrate Dehydrogenase 2 Inhibitors for the treatment of Hematologic Malignancies: Advances and Future Opportunities

2020 ◽  
Vol 20 ◽  
Author(s):  
Feng Huang ◽  
Tian Tian ◽  
Yizhe Wu ◽  
Jinxin Che ◽  
Haiyan Yang ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Oxidative Phosphorylation ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Metabolic Activity ◽  
Isocitrate Dehydrogenase ◽  
Clinical Studies ◽  
Recent Progress ◽  
Hematologic Malignancies ◽  
Isocitrate Dehydrogenase 2

: Tumor cells frequently reprogram cellular metabolism from oxidative phosphorylation to glycolysis. Isocitrate dehydrogenase 2 (IDH2) has been intensely studied due to its involvement in the metabolic activity of cancer cells. Mutations in IDH2 promote neomorphic activity through the generation of oncometabolite 2-hydroxyglutarate (2-HG). The overproduced 2-HG can competitively inhibit α-KG-dependent dioxygenases to trigger cell differentiation disorders, a major cause of blood tumors. This review outlines recent progress in the identification of IDH2 inhibitors in blood cancer to provide reference for ongoing and future clinical studies.

scholarly journals Hyperthermia combined chemotherapy regulates energy metabolism of cancer cells under hypoxic microenvironment

2020 ◽  
Author(s):  
Fan Shi ◽  
Dan Luo ◽  
Zhou Xuexiao ◽  
Qiaozhen Sun ◽  
Pei Shen ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Malignant Tumors ◽  
Tumor Therapy ◽  
High Mobility ◽  
Advanced Malignancy ◽  
Incidence And Mortality

Abstract Objective: Oral squamous cell carcinoma (OSCC) represents one of the main types of head and neck malignant tumors with high incidence and mortality as well extremely poor prognosis. Hyperthermia (HT) shows great promises for tumor therapy. However it can promote autophagy in tumor microenvironment, which is found to serve as a surviving mechanism for cancer cells. Inhibiting autophagy has been considered as an adjuvant anti-cancer strategy. The present study investigated the role of HT-induced autophagy, while attempting to combine chemotherapy and autophagy blocking with HT in OSCC cells under hypoxia and starvation microenvironment.Materials and methods: HIF-1α and Beclin-1 expression in tissues was determined by immunohistochemistry in 80 OSCC sample pairs. The IC50 of CoCl2, YC-1 (an inhibitor of HIF-1α) and 3-MA (an inhibitor of autophagy) was detected by CCK-8. CoCl2 and complete culture medium without serum were used to achieve the hypoxic and nutrient deficient microenvironment, respectively. HT was performed by heating in a 42 ℃ water bath. The role of HT and YC-1,3-MA on autophagy in vitro were assessed by qRT-PCR and Western blot, and the secretion of high mobility group box1 (HMGB1) was determined by ELISA. The migration and apoptosis rates of cells were assessed by wound healing assay and flow cytometry.Results: We observed that HIF-1α and Beclin1 were highly expressed in OSCC tissues, which were correlated with more advanced malignancy features. CoCl2 could establish hypoxia microenvironment, induce HIF-1α expression with dose-dependence as well as promote cell migration in Cal-27 and SCC-15 cells. Notably, hyperthermia and hypoxia could activate the HIF-1α/BNIP3/Beclin1 signaling pathway and promote HMGB1 secretion, which triggered cytoprotective autophagy to counteract the hypoxia and starvation cellular stresses, as indicated by downregulation of p62 and light chain 3-II (LC3 II). Furthermore, we found that hyperthermia combined YC-1 and/or 3-MA suppressed autophagy and cell migration whereas facilitated cell apoptosis.Conclusion: The present study demonstrated that combined use of YC-1 and 3-MA might increase death of tumor cells in physiological and hyperthermia conditions, which could be relevant with the inhibition of autophagy in OSCC tumor cells under hypoxia microenvironment in vitro.

scholarly journals Extracellular citrate and metabolic adaptations of cancer cells

2021 ◽  
Author(s):  
E. Kenneth Parkinson ◽  
Jerzy Adamski ◽  
Grit Zahn ◽  
Andreas Gaumann ◽  
Fabian Flores-Borja ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Cancer Cells ◽  
Immune Cells ◽  
Warburg Effect ◽  
Cancer Metabolism ◽  
Krebs Cycle ◽  
Therapy Resistance ◽  
Tumour Microenvironment ◽  
The Warburg Effect

Abstract It is well established that cancer cells acquire energy via the Warburg effect and oxidative phosphorylation. Citrate is considered to play a crucial role in cancer metabolism by virtue of its production in the reverse Krebs cycle from glutamine. Here, we review the evidence that extracellular citrate is one of the key metabolites of the metabolic pathways present in cancer cells. We review the different mechanisms by which pathways involved in keeping redox balance respond to the need of intracellular citrate synthesis under different extracellular metabolic conditions. In this context, we further discuss the hypothesis that extracellular citrate plays a role in switching between oxidative phosphorylation and the Warburg effect while citrate uptake enhances metastatic activities and therapy resistance. We also present the possibility that organs rich in citrate such as the liver, brain and bones might form a perfect niche for the secondary tumour growth and improve survival of colonising cancer cells. Consistently, metabolic support provided by cancer-associated and senescent cells is also discussed. Finally, we highlight evidence on the role of citrate on immune cells and its potential to modulate the biological functions of pro- and anti-tumour immune cells in the tumour microenvironment. Collectively, we review intriguing evidence supporting the potential role of extracellular citrate in the regulation of the overall cancer metabolism and metastatic activity.

scholarly journals Cancer Stem Cell-Associated Pathways in the Metabolic Reprogramming of Breast Cancer

2020 ◽  
Vol 21 (23) ◽  
pp. 9125
Author(s):  
Sara El-Sahli ◽  
Lisheng Wang
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Malignant Tumors ◽  
Metabolic Reprogramming ◽  
Metabolic Adaptation ◽  
Metabolic Flexibility ◽  
Tumor Initiating Cells ◽  
Metabolic Adaptations

Metabolic reprogramming of cancer is now considered a hallmark of many malignant tumors, including breast cancer, which remains the most commonly diagnosed cancer in women all over the world. One of the main challenges for the effective treatment of breast cancer emanates from the existence of a subpopulation of tumor-initiating cells, known as cancer stem cells (CSCs). Over the years, several pathways involved in the regulation of CSCs have been identified and characterized. Recent research has also shown that CSCs are capable of adopting a metabolic flexibility to survive under various stressors, contributing to chemo-resistance, metastasis, and disease relapse. This review summarizes the links between the metabolic adaptations of breast cancer cells and CSC-associated pathways. Identification of the drivers capable of the metabolic rewiring in breast cancer cells and CSCs and the signaling pathways contributing to metabolic flexibility may lead to the development of effective therapeutic strategies. This review also covers the role of these metabolic adaptation in conferring drug resistance and metastasis in breast CSCs.

scholarly journals Modulation of Autophagy in Cancer Cells by Dietary Polyphenols

Antioxidants ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 123
Author(s):  
Claudia Musial ◽  
Kamila Siedlecka-Kroplewska ◽  
Zbigniew Kmiec ◽  
Magdalena Gorska-Ponikowska
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Polyphenolic Compounds ◽  
In Vivo Studies ◽  
Cancer Disease ◽  
Protective Function ◽  
Dietary Polyphenols

The role of autophagy is to degrade damaged or unnecessary cellular structures. Both in vivo and in vitro studies suggest a dual role of autophagy in cancer—it may promote the development of neoplasms, but it may also play a tumor protective function. The mechanism of autophagy depends on the genetic context, tumor stage and type, tumor microenvironment, or clinical therapy used. Autophagy also plays an important role in cell death as well as in the induction of chemoresistance of cancer cells. The following review describes the extensive autophagic cell death in relation to dietary polyphenols and cancer disease. The review documents increasing use of polyphenolic compounds in cancer prevention, or as agents supporting oncological treatment. Polyphenols are organic chemicals that exhibit antioxidant, anti-inflammatory, anti-angiogenic, and immunomodulating properties, and can also initiate the process of apoptosis. In addition, polyphenols reduce oxidative stress and protect against reactive oxygen species. This review presents in vitro and in vivo studies in animal models with the use of polyphenolic compounds such as epigallocatechin-3-gallate (EGCG), oleuropein, punicalgin, apigenin, resveratrol, pterostilbene, or curcumin and their importance in the modulation of autophagy-induced death of cancer cells.

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