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Oncometabolite

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https://www.readbyqxmd.com/read/29671246/rapid-detection-of-mutation-in-isocitrate-dehydrogenase-1-and-2-genes-using-mass-spectrometry
#1
Masayuki Kanamori, Masamitsu Maekawa, Ichiyo Shibahara, Ryuta Saito, Masashi Chonan, Miki Shimada, Yukihiko Sonoda, Toshihiro Kumabe, Mika Watanabe, Nariyasu Mano, Teiji Tominaga
The 2016 World Health Organization classification of tumors of the central nervous system was recently revised. Mutations in the isocitrate dehydrogenase 1 (IDH1) and IDH2 genes and chromosome 1p/19q codeletion are especially important for both the integrated diagnosis and the determination of surgical strategy. To establish a method for intraoperative molecular diagnosis, a simple, rapid method was developed for the measurement of 2-hydroxyglutarate (2-HG), a specific oncometabolite formed in the presence of IDH gene mutation, using liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS)...
April 18, 2018: Brain Tumor Pathology
https://www.readbyqxmd.com/read/29670690/discovery-of-ag-120-ivosidenib-a-first-in-class-mutant-idh1-inhibitor-for-the-treatment-of-idh1-mutant-cancers
#2
Janeta Popovici-Muller, René M Lemieux, Erin Artin, Jeffrey O Saunders, Francesco G Salituro, Jeremy Travins, Giovanni Cianchetta, Zhenwei Cai, Ding Zhou, Dawei Cui, Ping Chen, Kimberly Straley, Erica Tobin, Fang Wang, Muriel D David, Virginie Penard-Lacronique, Cyril Quivoron, Véronique Saada, Stéphane de Botton, Stefan Gross, Lenny Dang, Hua Yang, Luke Utley, Yue Chen, Hyeryun Kim, Shengfang Jin, Zhiwei Gu, Gui Yao, Zhiyong Luo, Xiaobing Lv, Cheng Fang, Liping Yan, Andrew Olaharski, Lee Silverman, Scott Biller, Shin-San M Su, Katharine Yen
Somatic point mutations at a key arginine residue (R132) within the active site of the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) confer a novel gain of function in cancer cells, resulting in the production of d-2-hydroxyglutarate (2-HG), an oncometabolite. Elevated 2-HG levels are implicated in epigenetic alterations and impaired cellular differentiation. IDH1 mutations have been described in an array of hematologic malignancies and solid tumors. Here, we report the discovery of AG-120 (ivosidenib), an inhibitor of the IDH1 mutant enzyme that exhibits profound 2-HG lowering in tumor models and the ability to effect differentiation of primary patient AML samples ex vivo...
April 12, 2018: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29657328/non-canonical-functions-of-enzymes-facilitate-cross-talk-between-cell-metabolic-and-regulatory-pathways
#3
REVIEW
Marteinn T Snaebjornsson, Almut Schulze
The metabolic rewiring that occurs during cell transformation is a hallmark of cancer. It is diverse in different cancers as it reflects different combinations of oncogenic drivers, tumor suppressors, and the microenvironment. Metabolic rewiring is essential to cancer as it enables uncontrolled proliferation and adaptation to the fluctuating availability of nutrients and oxygen caused by poor access to the vasculature due to tumor growth and a foreign microenvironment encountered during metastasis. Increasing evidence now indicates that the metabolic state in cancer cells also plays a causal role in tumor growth and metastasis, for example through the action of oncometabolites, which modulate cell signaling and epigenetic pathways to promote malignancy...
April 16, 2018: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/29643764/the-idh1-mutation-induced-oncometabolite-2-hydroxyglutarate-may-affect-dna-methylation-and-expression-of-pd-l1-in-gliomas
#4
Luyan Mu, Yu Long, Changlin Yang, Linchun Jin, Haipeng Tao, Haitao Ge, Yifan E Chang, Aida Karachi, Paul S Kubilis, Gabriel De Leon, Jiping Qi, Elias J Sayour, Duane A Mitchell, Zhiguo Lin, Jianping Huang
Background: Malignant gliomas are heterogeneous brain tumors with the potential for aggressive disease progression, as influenced by suppressive immunoediting. Given the success and enhanced potential of immune-checkpoint inhibitors in immunotherapy, we focused on the connections between genetic alterations affected by IDH1 mutations and immunological landscape changes and PDL-1 expression in gliomas. Methods: Paired surgically resected tumors from lower-grade gliomas (LGGs) and glioblastomas (GBM) were investigated, and a genetic analysis of patients' primary tumor samples culled from TCGA datasets was performed...
2018: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/29626092/identification-of-a-metabolic-disposal-route-for-the-oncometabolite-s-2-succino-cysteine-in-bacillus-subtilis
#5
Thomas D Niehaus, Jacob Folz, Donald R McCarty, Arthur J L Cooper, David Moraga Amador, Oliver Fiehn, Andrew D Hanson
Cellular thiols such as cysteine spontaneously and readily react with the respiratory intermediate fumarate, resulting in the formation of stable S -(2-succino)-adducts. Fumarate-mediated succination of thiols increases in certain tumors and in response to glucotoxicity associated with diabetes. Therefore, S -(2-succino)-adducts such as S -(2-succino)cysteine (2SC) are considered oncometabolites and biomarkers for human disease. No disposal routes for S -(2-succino) compounds have been reported prior to this study...
April 6, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29619216/mutant-idh1-gliomas-downregulate-phosphocholine-and-phosphoethanolamine-synthesis-in-a-2-hydroxyglutarate-dependent-manner
#6
Pavithra Viswanath, Marina Radoul, Jose Luis Izquierdo-Garcia, Hema Artee Luchman, J Gregory Cairncross, Russell O Pieper, Joanna J Phillips, Sabrina M Ronen
Background: Magnetic resonance spectroscopy (MRS) studies have identified elevated levels of the phospholipid precursor phosphocholine (PC) and phosphoethanolamine (PE) as metabolic hallmarks of cancer. Unusually, however, PC and PE levels are reduced in mutant isocitrate dehydrogenase 1 (IDHmut) gliomas that produce the oncometabolite 2-hydroxyglutarate (2-HG) relative to wild-type IDH1 (IDHwt) gliomas. The goal of this study was to determine the molecular mechanism underlying this unusual metabolic reprogramming in IDHmut gliomas...
2018: Cancer & Metabolism
https://www.readbyqxmd.com/read/29599405/transketolase-regulates-the-metabolic-switch-to-control-breast-cancer-cell-metastasis-via-the-alpha-ketoglutarate-signaling-pathway
#7
Lu-Hai Wang, Chien-Wei Tseng, Wen-Hung Kuo, Shih-Hsuan Chan, Hong-Lin Chan, King-Jen Chang
Although metabolic reprogramming is recognized as a hallmark of tumorigenesis and progression, little is known about metabolic enzymes and oncometabolites that regulate breast cancer metastasis, and very few metabolic molecules have been identified as potential therapeutic targets. In this study, the transketolase (TKT) expression correlated with tumor size in the 4T1/BALB/c syngeneic model. In addition, TKT expression was higher in lymph node metastases compared with primary tumor or normal tissues of patients, and high TKT levels were associated with poor survival...
March 29, 2018: Cancer Research
https://www.readbyqxmd.com/read/29594839/o-glcnac-in-cancer-an-oncometabolism-fueled-vicious-cycle
#8
REVIEW
John A Hanover, Weiping Chen, Michelle R Bond
Cancer cells exhibit unregulated growth, altered metabolism, enhanced metastatic potential and altered cell surface glycans. Fueled by oncometabolism and elevated uptake of glucose and glutamine, the hexosamine biosynthetic pathway (HBP) sustains glycosylation in the endomembrane system. In addition, the elevated pools of UDP-GlcNAc drives the O-GlcNAc modification of key targets in the cytoplasm, nucleus and mitochondrion. These targets include transcription factors, kinases, key cytoplasmic enzymes of intermediary metabolism, and electron transport chain complexes...
March 29, 2018: Journal of Bioenergetics and Biomembranes
https://www.readbyqxmd.com/read/29564224/the-role-of-mitochondrial-h-atp-synthase-in-cancer
#9
REVIEW
Pau B Esparza-Moltó, José M Cuezva
Cancer cells reprogram energy metabolism by boosting aerobic glycolysis as a main pathway for the provision of metabolic energy and of precursors for anabolic purposes. Accordingly, the relative expression of the catalytic subunit of the mitochondrial H+ -ATP synthase-the core hub of oxidative phosphorylation-is downregulated in human carcinomas when compared with its expression in normal tissues. Moreover, some prevalent carcinomas also upregulate the ATPase inhibitory factor 1 (IF1), which is the physiological inhibitor of the H+ -ATP synthase...
2018: Frontiers in Oncology
https://www.readbyqxmd.com/read/29555211/inhibition-of-mtor-complexes-protects-cancer-cells-from-glutamine-starvation-induced-cell-death-by-restoring-akt-stability
#10
Wasim Khan, Brian T Layden, Partha Chakrabarti
Glutamine, a well-established oncometabolite, anaplerotically fuels mitochondrial energy metabolism and modulates activity of mammalian/mechanistic target of rapamycin complexes (mTOR). Currently, mTOR inhibitors are in clinical use for certain types of cancer but with limited success. Since glutamine is essential for growth of many cancers, we reasoned that glutamine deprivation under conditions of mTOR inhibition should be more detrimental to cancer cell survival. However, our results show that when cells are deprived of glutamine concomitant with mTOR inhibition, hepatocarcinoma cells elicit an adaptive response which aids in their survival due to enhanced autophagic flux...
March 16, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29545476/d-2-hydroxyglutarate-is-necessary-and-sufficient-for-isocitrate-dehydrogenase-1-mutant-induced-mir148a-promoter-methylation
#11
Tie Li, Christopher D Cox, Byram Ozer, Nhung T Nguyen, Huytram N Nguyen, Thomas J Lai, Sichen Li, Fei Liu, Harley I Kornblum, Linda M Liau, Phioanh Leia Nghiemphu, Timothy F Cloughesy, Albert Lai
Mutant isocitrate dehydrogenase (IDH) 1/2 converts α-ketoglutarate (α-KG) to D-2 hydroxyglutarate (D-2-HG), a putative oncometabolite that can inhibit α-KG dependent enzymes, including ten-eleven translocation methylcytosine dioxygenase (TET) DNA demethylases. We recently established that miRNAs are components of the IDH1 mutant-associated glioma CpG island methylator phenotype (G-CIMP), and specifically identified MIR148A as a tumor-suppressive miRNA within G-CIMP. However, the precise mechanism by which mutant IDH induces hypermethylation of MIR148A and other G-CIMP promoters remains to be elucidated...
March 15, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29544107/prediction-of-platinum-based-chemotherapy-efficacy-in-lung-cancer-based-on-lc-ms-metabolomics-approach
#12
Feng Peng, Yingzi Liu, Chenjie He, Yi Kong, Qianying Ouyang, Xiaonv Xie, Tong Liu, Zhaoqian Liu, Jingbo Peng
Lung cancer is the common cause of cancer-related death worldwide. Platinum-based chemotherapy is the cornerstone of treatment for lung cancer. Platinum sensitivity is a major possibility for effective cancer treatment. In this study, several potential biomarkers were identified for evaluating and predicting the response to platinum-based chemotherapy. LC-MS-based metabolomics was performed on plasma samples from 43 lung cancer patients with different chemotherapy efficacy. By combing multivariate statistical analysis, pathway analysis with correlation analysis, 8 potential biomarkers were significantly associated with platinum chemotherapy response...
February 23, 2018: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/29543066/the-role-of-idh-mutations-in-acute-myeloid-leukemia
#13
Guillermo Montalban-Bravo, Courtney D DiNardo
Isocitrate dehydrogenases (IDHs) are enzymes involved in multiple metabolic and epigenetic cellular processes. Mutations in IDH1 or IDH2 are detected in approximately 20% of patients with acute myeloid leukemia (AML) and induce amino acid changes in conserved residues resulting in neomorphic enzymatic function and production of an oncometabolite, 2-hydroxyglutarate (R-2-HG). This leads to DNA hypermethylation, aberrant gene expression, cell proliferation and abnormal differentiation. IDH mutations diversely affect prognosis of patients with AML based on the location of the mutation and other co-occurring genomic abnormalities...
March 15, 2018: Future Oncology
https://www.readbyqxmd.com/read/29514096/targeting-a-sirt5-positive-subpopulation-overcomes-multidrug-resistance-in-wild-type-kras-colorectal-carcinomas
#14
ZunGuo Du, XiuJuan Liu, Tao Chen, WenChao Gao, ZhengMing Wu, ZhiQian Hu, Dong Wei, ChunFang Gao, QingQuan Li
A major obstacle for successful management of patients with colorectal carcinoma (CRC) is resistance to anti-cancer cytotoxic treatments. Here, we identified a mechanism of multidrug resistance in wild-type Kras CRCs based on the survival of a cell subpopulation characterized by Sirt5 expression. Sirt5+ cells in wild-type Kras CRCs are resistant to either chemotherapeutic agents or cetuximab and serve as a reservoir for recurrence. Sirt5 demalonylates and inactivates succinate dehydrogenase complex subunit A (SDHA), leading to an accumulation of the oncometabolite succinate...
March 6, 2018: Cell Reports
https://www.readbyqxmd.com/read/29468929/tumor-derived-lactate-induces-m2-macrophage-polarization-via-the-activation-of-the-erk-stat3-signaling-pathway-in-breast-cancer
#15
Xianmin Mu, Wei Shi, Yue Xu, Che Xu, Ting Zhao, Biao Geng, Jing Yang, Jinshun Pan, Shi Hu, Chen Zhang, Juan Zhang, Chao Wang, Jiajia Shen, Yin Che, Zheng Liu, Yuanfang Lv, Hao Wen, Qiang You
Tumor-associated macrophages (TAM) are prominent components of tumor microenvironment (TME) and capable of promoting cancer progression. However, the mechanisms for the formation of M2-like TAMs remain enigmatic. Here, we show that lactate is a pivotal oncometabolite in the TME that drives macrophage M2-polarization to promote breast cancer proliferation, migration, and angiogenesis. In addition, we identified that the activation of ERK/ STAT3, major signaling molecules in the lactate signaling pathway, deepens our molecular understanding of how lactate educates TAMs...
February 22, 2018: Cell Cycle
https://www.readbyqxmd.com/read/29467457/adenylosuccinate-lyase-enhances-aggressiveness-of-endometrial-cancer-by-increasing-killer-cell-lectin-like-receptor-c3-expression-by-fumarate
#16
Haengki Park, Kenji Ohshima, Satoshi Nojima, Shinichiro Tahara, Masako Kurashige, Yumiko Hori, Daisuke Okuzaki, Naoki Wada, Jun-Ichiro Ikeda, Eiichi Morii
Adenylosuccinate lyase (ADSL) is an enzyme that plays important roles in de novo purine synthesis. Although ADSL was reported to be upregulated in various malignancies, such as colorectal, breast, and prostate cancer, as well as gliomas, the mechanism by which elevated ADSL expression contributes to cancer has not been elucidated. We previously performed a shotgun proteomics analysis to characterize specific proteins associated with the properties of the aldehyde dehydrogenase (ALDH)-high cell population, which was reported to be involved in tumorigenic potential, and showed that ADSL expression is upregulated in the ALDH-high population of endometrial cancer...
February 21, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/29409060/pheochromocytoma-paraganglioma-a-poster-child-for-cancer-metabolism
#17
Sergei G Tevosian, Hans K Ghayee
Context: Pheochromocytomas (PCCs) are tumors that are derived from the chromaffin cells of the adrenal medulla. Extra-adrenal PCCs called paragangliomas (PGLs) are derived from the sympathetic and parasympathetic chain ganglia. PCCs secrete catecholamines which cause hypertension and have adverse cardiovascular consequences as a result of catecholamine excess. PGLs may or may not produce catecholamines depending on their genetic type and anatomical location. The most worrisome aspect of these tumors is their ability to become aggressive and metastasize, for which there are no known cures...
February 1, 2018: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/29382206/tof-sims-analysis-of-an-isocitrate-dehydrogenase-1-mutation-associated-oncometabolite-in-cancer-cells
#18
Jungdae Park, Hee-Kyung Na, Hyun Kyong Shon, Hye Young Son, Yong-Min Huh, Sang-Won Lee, Tae Geol Lee
The development of analytical tools for accurate and sensitive detection of intracellular metabolites associated with mutated metabolic enzymes is important in cancer diagnosis and staging. The gene encoding the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) is mutated in various cancers, and mutant IDH1 could represent a good biomarker and potent target for cancer therapy. Owing to a mutation in an important arginine residue in the catalytic pocket, mutant IDH1 catalyzes the production of 2-hydroxyglutarate (2-HG) instead of its wild type product α-ketoglutarate (α-KG), which is involved in multiple cellular pathways involving the hydroxylation of proteins, ribonucleic acid, and deoxyribose nucleic acid (DNA)...
January 30, 2018: Biointerphases
https://www.readbyqxmd.com/read/29367352/seeding-of-proteins-into-amyloid-structures-by-metabolite-assemblies-may-clarify-certain-unexplained-epidemiological-associations
#19
REVIEW
Dorin Sade, Shira Shaham-Niv, Zohar A Arnon, Omid Tavassoly, Ehud Gazit
The accumulation of various metabolites appears to be associated with diverse human diseases. However, the aetiological link between metabolic alteration and the observed diseases is still elusive. This includes the correlation between the abnormally high levels of homocysteine and quinolinic acid in Alzheimer's disease, as well as the accumulation of oncometabolites in malignant processes. Here, we suggest and discuss a possible mechanistic insight into metabolite accumulation in conditions such as neurodegenerative diseases and cancer...
January 2018: Open Biology
https://www.readbyqxmd.com/read/29358170/2-hydroxyglutarate-mediated-autophagy-of-the-endoplasmic-reticulum-leads-to-an-unusual-downregulation-of-phospholipid-biosynthesis-in-mutant-idh1-gliomas
#20
Pavithra Viswanath, Marina Radoul, Jose Luis Izquierdo-Garcia, Wei Qiang Ong, Hema Artee Luchman, John Gregory Cairncross, Bo Huang, Russell O Pieper, Joanna J Phillips, Sabrina M Ronen
Tumor metabolism is reprogrammed to meet the demands of proliferating cancer cells. In particular, cancer cells upregulate synthesis of the membrane phospholipids phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdE) in order to allow for rapid membrane turnover. Nonetheless, we show here that, in mutant isocitrate dehydrogenase 1 (IDHmut) gliomas, which produce the oncometabolite 2-hydroxyglutarate (2-HG), PtdCho and PtdE biosynthesis is downregulated and results in lower levels of both phospholipids when compared to wild-type IDH1 cells...
January 22, 2018: Cancer Research
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