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Alorjani MS, Al Bashir S, Al-Zaareer B, Al-Khatib S, Al-Zoubi RM, Al-Trad B, AbuAlarja M, Alzu’bi A, Al-Hamad M, Al-Batayneh K, Al-Zoubi MS. Prevalence of SPOP and IDH Gene Mutations in Prostate Cancer in a Jordanian Population. Biochem Genet 2024. [DOI: 10.1007/s10528-024-10974-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 11/04/2024] [Indexed: 01/11/2025]
Abstract
AbstractSpeckle-type POZ (SPOP) is described as an essential tumor suppressor factor in gastric cancer, colorectal cancer, and prostate cancer (PCa). SPOP gene mutations were reported in primary human PCa. Isocitrate dehydrogenase-1 (IDH1) oncogene mutations were detected in gliomas, acute myeloid leukemia, some benign and malignant cartilaginous tumors, and only 1% of PCa. This study aimed to investigate the prevalence of mutations of SPOP and IDH1 genes in PCa in the Jordanian population. One hundred formalin-fixed paraffin-embedded tissue samples were collected from patients diagnosed with prostate adenocarcinoma. The obtained specimens were subjected to genomic DNA extraction, PCR amplification, and direct sequencing of exons 4, 5, 6, and 7 of the SPOP gene and exon 6 of the IDH1 gene. SPOP gene mutations were found in 17% of PCa cases, while no mutation was detected in the screened exon 6 of the IDH1 gene. Clinicopathological data demonstrated a strong correlation between prostate-specific antigen (PSA) levels and both Gleason score (GS) and the International Society of Urological Pathology (ISUP) grade group (GG). There was no significant correlation between PSA levels and age (p = 0.816) nor there were significant associations for SPOP mutational status with age (p = 0.659), PSA levels (p = 0.395), GS (p = 0.259), and ISUP GG (p = 0.424) in the tested population. The study found a strong correlation between PSA levels and both GS and ISUP GG. It also identified a high frequency (17%) of SPOP gene mutations in Jordanian Arab PCa patients, mainly in exon 7. No IDH1 mutations were detected in exon 6.
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Watts JM, Shaw SJ, Jonas BA. Looking Beyond the Surface: Olutasidenib and Ivosidenib for Treatment of mIDH1 Acute Myeloid Leukemia. Curr Treat Options Oncol 2024; 25:1345-1353. [PMID: 39406957 PMCID: PMC11541360 DOI: 10.1007/s11864-024-01264-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/15/2024] [Indexed: 11/07/2024]
Abstract
OPINION STATEMENT Mutations in isocitrate dehydrogenase-1 (IDH1) are recurrent in several malignancies and prevalent in acute myeloid leukemia (AML). Olutasidenib and ivosidenib are inhibitors that target mutant IDH1 (mIDH1) and are FDA approved for the treatment of patients with mIDH1 AML. Olutasidenib and ivosidenib were identified through unique molecular screens and thus are structurally very different molecules. A difference in clinical outcomes has been observed with olutasidenib, which has a longer duration of response than ivosidenib, despite similar rates of response being achieved with the two drugs, such as complete remission (CR) or CR with partial hematologic recovery (CR/CRh). In the absence of a head-to-head trial, this review examines both the extent of differences in clinical outcomes with the two drugs and provides the first comparison of the unique molecular and mechanistic features of each drug, such as molecular structure and binding kinetics, that may contribute to the observed clinical difference in outcomes. Olutasidenib is structurally smaller with a lower molecular weight than ivosidenib (FW 355 vs FW 583) and thus occupies less space in the binding pocket of IDH1 dimers, making it resistant to displacement by IDH1 second-site mutations. In biochemical studies, olutasidenib selectively inhibits mutant but not wild-type IDH1, whereas ivosidenib appears to potently block both mutant and wild-type IDH1. Although they have the same target, olutasidenib and ivosidenib have unique molecular features, which may translate to selectivity differences in their inhibitory activity against IDH1.
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Affiliation(s)
- Justin M Watts
- Sylvester Comprehensive Cancer Center, Division of Hematology, University of Miami, 1475 Northwest 12th Ave, Miami, FL, 33136, USA.
| | - Simon J Shaw
- Rigel Pharmaceuticals, Inc., South San Francisco, CA, USA
| | - Brian A Jonas
- UC Davis Comprehensive Cancer Center, University of California, Davis Sacramento, CA, USA
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3
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Mealka M, Sierra NA, Avellaneda Matteo D, Albekioni E, Khoury R, Mai T, Conley BM, Coleman NJ, Sabo KA, Komives EA, Bobkov AA, Cooksy AL, Silletti S, Schiffer JM, Huxford T, Sohl CD. Active site remodeling in tumor-relevant IDH1 mutants drives distinct kinetic features and potential resistance mechanisms. Nat Commun 2024; 15:3785. [PMID: 38710674 PMCID: PMC11074275 DOI: 10.1038/s41467-024-48277-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 04/26/2024] [Indexed: 05/08/2024] Open
Abstract
Mutations in human isocitrate dehydrogenase 1 (IDH1) drive tumor formation in a variety of cancers by replacing its conventional activity with a neomorphic activity that generates an oncometabolite. Little is understood of the mechanistic differences among tumor-driving IDH1 mutants. We previously reported that the R132Q mutant unusually preserves conventional activity while catalyzing robust oncometabolite production, allowing an opportunity to compare these reaction mechanisms within a single active site. Here, we employ static and dynamic structural methods and observe that, compared to R132H, the R132Q active site adopts a conformation primed for catalysis with optimized substrate binding and hydride transfer to drive improved conventional and neomorphic activity over R132H. This active site remodeling reveals a possible mechanism of resistance to selective mutant IDH1 therapeutic inhibitors. This work enhances our understanding of fundamental IDH1 mechanisms while pinpointing regions for improving inhibitor selectivity.
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Affiliation(s)
- Matthew Mealka
- Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA
| | - Nicole A Sierra
- Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA
| | | | - Elene Albekioni
- Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA
| | - Rachel Khoury
- Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA
| | - Timothy Mai
- Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA
| | - Brittany M Conley
- Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA
| | - Nalani J Coleman
- Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA
| | - Kaitlyn A Sabo
- Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA
| | - Elizabeth A Komives
- Department of Chemistry & Biochemistry, University of California San Diego, La Jolla, CA, USA
| | - Andrey A Bobkov
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Andrew L Cooksy
- Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA
| | - Steve Silletti
- Department of Chemistry & Biochemistry, University of California San Diego, La Jolla, CA, USA
| | | | - Tom Huxford
- Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA
| | - Christal D Sohl
- Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA.
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4
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Kitagawa Y, Kobayashi A, Cahill DP, Wakimoto H, Tanaka S. Molecular biology and novel therapeutics for IDH mutant gliomas: The new era of IDH inhibitors. Biochim Biophys Acta Rev Cancer 2024; 1879:189102. [PMID: 38653436 DOI: 10.1016/j.bbcan.2024.189102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 03/25/2024] [Accepted: 04/16/2024] [Indexed: 04/25/2024]
Abstract
Gliomas with Isocitrate dehydrogenase (IDH) mutation represent a discrete category of primary brain tumors with distinct and unique characteristics, behaviors, and clinical disease outcomes. IDH mutations lead to aberrant high-level production of the oncometabolite D-2-hydroxyglutarate (D-2HG), which act as a competitive inhibitor of enzymes regulating epigenetics, signaling pathways, metabolism, and various other processes. This review summarizes the significance of IDH mutations, resulting upregulation of D-2HG and the associated molecular pathways in gliomagenesis. With the recent finding of clinically effective IDH inhibitors in these gliomas, this article offers a comprehensive overview of the new era of innovative therapeutic approaches based on mechanistic rationales, encompassing both completed and ongoing clinical trials targeting gliomas with IDH mutations.
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Affiliation(s)
- Yosuke Kitagawa
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, 02114 Boston, MA, USA; Translational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, 02114 Boston, MA, USA; Department of Neurosurgery, Graduate School of Medicine, The University of Tokyo, 1138655 Bunkyo-ku, Tokyo, Japan
| | - Ami Kobayashi
- Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, 02115 Boston, MA, USA
| | - Daniel P Cahill
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, 02114 Boston, MA, USA; Translational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, 02114 Boston, MA, USA
| | - Hiroaki Wakimoto
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, 02114 Boston, MA, USA; Translational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, 02114 Boston, MA, USA.
| | - Shota Tanaka
- Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 7008558, Okayama, Japan
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5
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Mealka M, Sierra NA, Matteo DA, Albekioni E, Khoury R, Mai T, Conley BM, Coleman NJ, Sabo KA, Komives EA, Bobkov AA, Cooksy AL, Silletti S, Schiffer JM, Huxford T, Sohl CD. Active site remodeling in tumor-relevant IDH1 mutants drives distinct kinetic features and potential resistance mechanisms. RESEARCH SQUARE 2024:rs.3.rs-3889456. [PMID: 38464189 PMCID: PMC10925425 DOI: 10.21203/rs.3.rs-3889456/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/12/2024]
Abstract
Mutations in human isocitrate dehydrogenase 1 (IDH1) drive tumor formation in a variety of cancers by replacing its conventional activity with a neomorphic activity that generates an oncometabolite. Little is understood of the mechanistic differences among tumor-driving IDH1 mutants. We previously reported that the R132Q mutant uniquely preserves conventional activity while catalyzing robust oncometabolite production, allowing an opportunity to compare these reaction mechanisms within a single active site. Here, we employed static and dynamic structural methods and found that, compared to R132H, the R132Q active site adopted a conformation primed for catalysis with optimized substrate binding and hydride transfer to drive improved conventional and neomorphic activity over R132H. This active site remodeling revealed a possible mechanism of resistance to selective mutant IDH1 therapeutic inhibitors. This work enhances our understanding of fundamental IDH1 mechanisms while pinpointing regions for improving inhibitor selectivity.
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Affiliation(s)
- Matthew Mealka
- Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA
| | - Nicole A. Sierra
- Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA
| | | | - Elene Albekioni
- Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA
| | - Rachel Khoury
- Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA
| | - Timothy Mai
- Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA
| | - Brittany M. Conley
- Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA
| | - Nalani J. Coleman
- Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA
| | - Kaitlyn A. Sabo
- Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA
| | - Elizabeth A. Komives
- Department of Chemistry & Biochemistry, University of California San Diego, La Jolla, CA, USA
| | - Andrey A. Bobkov
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA USA
| | - Andrew L. Cooksy
- Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA
| | - Steve Silletti
- Department of Chemistry & Biochemistry, University of California San Diego, La Jolla, CA, USA
| | | | - Tom Huxford
- Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA
| | - Christal D. Sohl
- Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA
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Mealka M, Sierra NA, Matteo DA, Albekioni E, Khoury R, Mai T, Conley BM, Coleman NJ, Sabo KA, Komives EA, Bobkov AA, Cooksy AL, Silletti S, Schiffer JM, Huxford T, Sohl CD. Active site remodeling in tumor-relevant IDH1 mutants drives distinct kinetic features and potential resistance mechanisms. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.10.574970. [PMID: 38260668 PMCID: PMC10802581 DOI: 10.1101/2024.01.10.574970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2024]
Abstract
Mutations in human isocitrate dehydrogenase 1 (IDH1) drive tumor formation in a variety of cancers by replacing its conventional activity with a neomorphic activity that generates an oncometabolite. Little is understood of the mechanistic differences among tumor-driving IDH1 mutants. We previously reported that the R132Q mutant uniquely preserves conventional activity while catalyzing robust oncometabolite production, allowing an opportunity to compare these reaction mechanisms within a single active site. Here, we employed static and dynamic structural methods and found that, compared to R132H, the R132Q active site adopted a conformation primed for catalysis with optimized substrate binding and hydride transfer to drive improved conventional and neomorphic activity over R132H. This active site remodeling revealed a possible mechanism of resistance to selective mutant IDH1 therapeutic inhibitors. This work enhances our understanding of fundamental IDH1 mechanisms while pinpointing regions for improving inhibitor selectivity.
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Affiliation(s)
- Matthew Mealka
- Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA
| | - Nicole A. Sierra
- Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA
| | | | - Elene Albekioni
- Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA
| | - Rachel Khoury
- Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA
| | - Timothy Mai
- Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA
| | - Brittany M. Conley
- Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA
| | - Nalani J. Coleman
- Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA
| | - Kaitlyn A. Sabo
- Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA
| | - Elizabeth A. Komives
- Department of Chemistry & Biochemistry, University of California San Diego, La Jolla, CA, USA
| | - Andrey A. Bobkov
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA USA
| | - Andrew L. Cooksy
- Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA
| | - Steve Silletti
- Department of Chemistry & Biochemistry, University of California San Diego, La Jolla, CA, USA
| | | | - Tom Huxford
- Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA
| | - Christal D. Sohl
- Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA, USA
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7
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Yegambaram M, Sun X, Lu Q, Jin Y, Ornatowski W, Soto J, Aggarwal S, Wang T, Tieu K, Gu H, Fineman JR, Black SM. Mitochondrial hyperfusion induces metabolic remodeling in lung endothelial cells by modifying the activities of electron transport chain complexes I and III. Free Radic Biol Med 2024; 210:183-194. [PMID: 37979892 DOI: 10.1016/j.freeradbiomed.2023.11.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 11/02/2023] [Accepted: 11/11/2023] [Indexed: 11/20/2023]
Abstract
OBJECTIVE Pulmonary hypertension (PH) is a progressive disease with vascular remodeling as a critical structural alteration. We have previously shown that metabolic reprogramming is an early initiating mechanism in animal models of PH. This metabolic dysregulation has been linked to remodeling the mitochondrial network to favor fission. However, whether the mitochondrial fission/fusion balance underlies the metabolic reprogramming found early in PH development is unknown. METHODS Utilizing a rat early model of PH, in conjunction with cultured pulmonary endothelial cells (PECs), we utilized metabolic flux assays, Seahorse Bioassays, measurements of electron transport chain (ETC) complex activity, fluorescent microscopy, and molecular approaches to investigate the link between the disruption of mitochondrial dynamics and the early metabolic changes that occur in PH. RESULTS We observed increased fusion mediators, including Mfn1, Mfn2, and Opa1, and unchanged fission mediators, including Drp1 and Fis1, in a two-week monocrotaline-induced PH animal model (early-stage PH). We were able to establish a connection between increases in fusion mediator Mfn1 and metabolic reprogramming. Using an adenoviral expression system to enhance Mfn1 levels in pulmonary endothelial cells and utilizing 13C-glucose labeled substrate, we found increased production of 13C lactate and decreased TCA cycle metabolites, revealing a Warburg phenotype. The use of a 13C5-glutamine substrate showed evidence that hyperfusion also induces oxidative carboxylation. The increase in glycolysis was linked to increased hypoxia-inducible factor 1α (HIF-1α) protein levels secondary to the disruption of cellular bioenergetics and higher levels of mitochondrial reactive oxygen species (mt-ROS). The elevation in mt-ROS correlated with attenuated ETC complexes I and III activities. Utilizing a mitochondrial-targeted antioxidant to suppress mt-ROS, limited HIF-1α protein levels, which reduced cellular glycolysis and reestablished mitochondrial membrane potential. CONCLUSIONS Our data connects mitochondrial fusion-mediated mt-ROS to the Warburg phenotype in early-stage PH development.
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Affiliation(s)
- Manivannan Yegambaram
- Center for Translational Science, Florida International University, 11350 SW Village Parkway, Port St. Lucie, FL, 34987-2352, USA; Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL, 33199, USA
| | - Xutong Sun
- Center for Translational Science, Florida International University, 11350 SW Village Parkway, Port St. Lucie, FL, 34987-2352, USA; Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL, 33199, USA
| | - Qing Lu
- Center for Translational Science, Florida International University, 11350 SW Village Parkway, Port St. Lucie, FL, 34987-2352, USA; Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL, 33199, USA
| | - Yan Jin
- Center for Translational Science, Florida International University, 11350 SW Village Parkway, Port St. Lucie, FL, 34987-2352, USA
| | | | - Jamie Soto
- Center for Translational Science, Florida International University, 11350 SW Village Parkway, Port St. Lucie, FL, 34987-2352, USA
| | - Saurabh Aggarwal
- Department of Cellular Biology & Pharmacology, Howard Wertheim College of Medicine, Florida International University, Miami, FL, 33199, USA
| | - Ting Wang
- Center for Translational Science, Florida International University, 11350 SW Village Parkway, Port St. Lucie, FL, 34987-2352, USA; Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL, 33199, USA; Department of Cellular Biology & Pharmacology, Howard Wertheim College of Medicine, Florida International University, Miami, FL, 33199, USA
| | - Kim Tieu
- Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL, 33199, USA
| | - Haiwei Gu
- Center for Translational Science, Florida International University, 11350 SW Village Parkway, Port St. Lucie, FL, 34987-2352, USA; Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL, 33199, USA
| | - Jeffrey R Fineman
- Department of Pediatrics, University of California San Francisco, San Francisco, CA, 94143, USA; Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Stephen M Black
- Center for Translational Science, Florida International University, 11350 SW Village Parkway, Port St. Lucie, FL, 34987-2352, USA; Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL, 33199, USA; Department of Cellular Biology & Pharmacology, Howard Wertheim College of Medicine, Florida International University, Miami, FL, 33199, USA.
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8
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Guo Z, Huo X, Li X, Jiang C, Xue L. Advances in regulation and function of stearoyl-CoA desaturase 1 in cancer, from bench to bed. SCIENCE CHINA. LIFE SCIENCES 2023; 66:2773-2785. [PMID: 37450239 DOI: 10.1007/s11427-023-2352-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Accepted: 04/23/2023] [Indexed: 07/18/2023]
Abstract
Stearoyl-CoA desaturase 1 (SCD1) converts saturated fatty acids to monounsaturated fatty acids. The expression of SCD1 is increased in many cancers, and the altered expression contributes to the proliferation, invasion, sternness and chemoresistance of cancer cells. Recently, more evidence has been reported to further support the important role of SCD1 in cancer, and the regulation mechanism of SCD1 has also been focused. Multiple factors are involved in the regulation of SCD1, including metabolism, diet, tumor microenvironment, transcription factors, non-coding RNAs, and epigenetics modification. Moreover, SCD1 is found to be involved in regulating ferroptosis resistance. Based on these findings, SCD1 has been considered as a potential target for cancer treatment. However, the resistance of SCD1 inhibition may occur in certain tumors due to tumor heterogeneity and metabolic plasticity. This review summarizes recent advances in the regulation and function of SCD1 in tumors and discusses the potential clinical application of targeting SCD1 for cancer treatment.
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Affiliation(s)
- Zhengyang Guo
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, 100191, China
| | - Xiao Huo
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, 100191, China
| | - Xianlong Li
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, 100191, China
| | - Changtao Jiang
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, 100191, China.
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University and the Key Laboratory of Molecular Cardiovascular Science (Peking University), Ministry of Education, Beijing, 100191, China.
| | - Lixiang Xue
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, 100191, China.
- Peking University Third Hospital Cancer Center, Department of Radiation Oncology, Peking University Third Hospital, Beijing, 100191, China.
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9
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Roma A, Goodridge LD, Spagnuolo PA. Reductive carboxylation of glutamine as a potential target in acute myeloid leukemia. Oncotarget 2023; 14:947-948. [PMID: 38039409 PMCID: PMC10691817 DOI: 10.18632/oncotarget.28474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Indexed: 12/03/2023] Open
Affiliation(s)
| | | | - Paul A. Spagnuolo
- Correspondence to:Paul A. Spagnuolo, Department of Food Science, University of Guelph, Guelph, Ontario N1G 2W1, Canada email
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10
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Mishra SK, Millman SE, Zhang L. Metabolism in acute myeloid leukemia: mechanistic insights and therapeutic targets. Blood 2023; 141:1119-1135. [PMID: 36548959 PMCID: PMC10375271 DOI: 10.1182/blood.2022018092] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 11/29/2022] [Accepted: 12/16/2022] [Indexed: 12/24/2022] Open
Abstract
Metabolic rewiring and cellular reprogramming are trademarks of neoplastic initiation and progression in acute myeloid leukemia (AML). Metabolic alteration in leukemic cells is often genotype specific, with associated changes in epigenetic and functional factors resulting in the downstream upregulation or facilitation of oncogenic pathways. Targeting abnormal or disease-sustaining metabolic activities in AML provides a wide range of therapeutic opportunities, ideally with enhanced therapeutic windows and robust clinical efficacy. This review highlights the dysregulation of amino acid, nucleotide, lipid, and carbohydrate metabolism in AML; explores the role of key vitamins and enzymes that regulate these processes; and provides an overview of metabolism-directed therapies currently in use or development.
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Affiliation(s)
| | - Scott E. Millman
- Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Lingbo Zhang
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
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11
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Thomas D, Wu M, Nakauchi Y, Zheng M, Thompson-Peach CA, Lim K, Landberg N, Köhnke T, Robinson N, Kaur S, Kutyna M, Stafford M, Hiwase D, Reinisch A, Peltz G, Majeti R. Dysregulated Lipid Synthesis by Oncogenic IDH1 Mutation Is a Targetable Synthetic Lethal Vulnerability. Cancer Discov 2023; 13:496-515. [PMID: 36355448 PMCID: PMC9900324 DOI: 10.1158/2159-8290.cd-21-0218] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 09/18/2022] [Accepted: 11/08/2022] [Indexed: 11/12/2022]
Abstract
Isocitrate dehydrogenase 1 and 2 (IDH) are mutated in multiple cancers and drive production of (R)-2-hydroxyglutarate (2HG). We identified a lipid synthesis enzyme [acetyl CoA carboxylase 1 (ACC1)] as a synthetic lethal target in mutant IDH1 (mIDH1), but not mIDH2, cancers. Here, we analyzed the metabolome of primary acute myeloid leukemia (AML) blasts and identified an mIDH1-specific reduction in fatty acids. mIDH1 also induced a switch to b-oxidation indicating reprogramming of metabolism toward a reliance on fatty acids. Compared with mIDH2, mIDH1 AML displayed depletion of NADPH with defective reductive carboxylation that was not rescued by the mIDH1-specific inhibitor ivosidenib. In xenograft models, a lipid-free diet markedly slowed the growth of mIDH1 AML, but not healthy CD34+ hematopoietic stem/progenitor cells or mIDH2 AML. Genetic and pharmacologic targeting of ACC1 resulted in the growth inhibition of mIDH1 cancers not reversible by ivosidenib. Critically, the pharmacologic targeting of ACC1 improved the sensitivity of mIDH1 AML to venetoclax. SIGNIFICANCE Oncogenic mutations in both IDH1 and IDH2 produce 2-hydroxyglutarate and are generally considered equivalent in terms of pathogenesis and targeting. Using comprehensive metabolomic analysis, we demonstrate unexpected metabolic differences in fatty acid metabolism between mutant IDH1 and IDH2 in patient samples with targetable metabolic interventions. See related commentary by Robinson and Levine, p. 266. This article is highlighted in the In This Issue feature, p. 247.
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Affiliation(s)
- Daniel Thomas
- Department of Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Palo Alto, California
- Adelaide Medical School, University of Adelaide, South Australia and Precision Medicine, South Australian Health and Medical Research Institute, Adelaide, Australia
| | - Manhong Wu
- Department of Anesthesiology, Pain and Perioperative Medicine, Stanford University School of Medicine, Palo Alto, California
| | - Yusuke Nakauchi
- Department of Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Palo Alto, California
| | - Ming Zheng
- Department of Anesthesiology, Pain and Perioperative Medicine, Stanford University School of Medicine, Palo Alto, California
| | - Chloe A.L. Thompson-Peach
- Adelaide Medical School, University of Adelaide, South Australia and Precision Medicine, South Australian Health and Medical Research Institute, Adelaide, Australia
| | - Kelly Lim
- Adelaide Medical School, University of Adelaide, South Australia and Precision Medicine, South Australian Health and Medical Research Institute, Adelaide, Australia
| | - Niklas Landberg
- Department of Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Palo Alto, California
| | - Thomas Köhnke
- Department of Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Palo Alto, California
| | - Nirmal Robinson
- Centre for Cancer Biology, University of South Australia, South Australia, Australia
| | - Satinder Kaur
- Department of Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Palo Alto, California
| | - Monika Kutyna
- Adelaide Medical School, University of Adelaide, South Australia and Precision Medicine, South Australian Health and Medical Research Institute, Adelaide, Australia
| | - Melissa Stafford
- Department of Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Palo Alto, California
| | - Devendra Hiwase
- Adelaide Medical School, University of Adelaide, South Australia and Precision Medicine, South Australian Health and Medical Research Institute, Adelaide, Australia
| | - Andreas Reinisch
- Department of Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Palo Alto, California
- Division of Hematology and Department of Blood Group Serology and Transfusion Medicine, Medical University of Graz, Graz, Austria
| | - Gary Peltz
- Department of Anesthesiology, Pain and Perioperative Medicine, Stanford University School of Medicine, Palo Alto, California
| | - Ravindra Majeti
- Department of Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Palo Alto, California
- Corresponding Author: Ravindra Majeti, Department of Medicine, Division of Hematology, Stanford Institute for Stem Cell Biology and Regenerative Medicine, Lokey Stem Cell Building, 265 Campus Drive, Stanford, CA 94305. Phone: 650-721-6376; Fax: 650-736-2961; E-mail:
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12
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He Q, Chen J, Xie Z, Chen Z. Wild-Type Isocitrate Dehydrogenase-Dependent Oxidative Decarboxylation and Reductive Carboxylation in Cancer and Their Clinical Significance. Cancers (Basel) 2022; 14:cancers14235779. [PMID: 36497259 PMCID: PMC9741289 DOI: 10.3390/cancers14235779] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 11/16/2022] [Accepted: 11/22/2022] [Indexed: 11/25/2022] Open
Abstract
The human isocitrate dehydrogenase (IDH) gene encodes for the isoenzymes IDH1, 2, and 3, which catalyze the conversion of isocitrate and α-ketoglutarate (α-KG) and are required for normal mammalian metabolism. Isocitrate dehydrogenase 1 and 2 catalyze the reversible conversion of isocitrate to α-KG. Isocitrate dehydrogenase 3 is the key enzyme that mediates the production of α-KG from isocitrate in the tricarboxylic acid (TCA) cycle. In the TCA cycle, the decarboxylation reaction catalyzed by isocitrate dehydrogenase mediates the conversion of isocitrate to α-KG accompanied by dehydrogenation, a process commonly known as oxidative decarboxylation. The formation of 6-C isocitrate from α-KG and CO2 catalyzed by IDH is termed reductive carboxylation. This IDH-mediated reversible reaction is of great importance in tumor cells. We outline the role of the various isocitrate dehydrogenase isoforms in cancer, discuss the metabolic implications of interference with IDH, summarize therapeutic interventions targeting changes in IDH expression, and highlight areas for future research.
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13
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Arai H, Minami Y, Chi S, Utsu Y, Masuda S, Aotsuka N. Molecular-Targeted Therapy for Tumor-Agnostic Mutations in Acute Myeloid Leukemia. Biomedicines 2022; 10:3008. [PMID: 36551764 PMCID: PMC9775249 DOI: 10.3390/biomedicines10123008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 11/09/2022] [Accepted: 11/14/2022] [Indexed: 11/24/2022] Open
Abstract
Comprehensive genomic profiling examinations (CGPs) have recently been developed, and a variety of tumor-agnostic mutations have been detected, leading to the development of new molecular-targetable therapies across solid tumors. In addition, the elucidation of hereditary tumors, such as breast and ovarian cancer, has pioneered a new age marked by the development of new treatments and lifetime management strategies required for patients with potential or presented hereditary cancers. In acute myeloid leukemia (AML), however, few tumor-agnostic or hereditary mutations have been the focus of investigation, with associated molecular-targeted therapies remaining poorly developed. We focused on representative tumor-agnostic mutations such as the TP53, KIT, KRAS, BRCA1, ATM, JAK2, NTRK3, FGFR3 and EGFR genes, referring to a CGP study conducted in Japan, and we considered the possibility of developing molecular-targeted therapies for AML with tumor-agnostic mutations. We summarized the frequency, the prognosis, the structure and the function of these mutations as well as the current treatment strategies in solid tumors, revealed the genetical relationships between solid tumors and AML and developed tumor-agnostic molecular-targeted therapies and lifetime management strategies in AML.
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Affiliation(s)
- Hironori Arai
- Department of Hematology and Oncology, Japanese Red Cross Narita Hospital, Iidacho 286-0041, Japan
- Department of Hematology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan
| | - Yosuke Minami
- Department of Hematology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan
| | - SungGi Chi
- Department of Hematology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan
| | - Yoshikazu Utsu
- Department of Hematology and Oncology, Japanese Red Cross Narita Hospital, Iidacho 286-0041, Japan
| | - Shinichi Masuda
- Department of Hematology and Oncology, Japanese Red Cross Narita Hospital, Iidacho 286-0041, Japan
| | - Nobuyuki Aotsuka
- Department of Hematology and Oncology, Japanese Red Cross Narita Hospital, Iidacho 286-0041, Japan
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14
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Ni Y, Shen P, Wang X, Liu H, Luo H, Han X. The roles of IDH1 in tumor metabolism and immunity. Future Oncol 2022; 18:3941-3953. [PMID: 36621781 DOI: 10.2217/fon-2022-0583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
IDH1 is a key metabolic enzyme for cellular respiration in the tricarboxylic acid (TCA) cycle that can convert isocitrate into α-ketoglutarate (α-KG) and generate NADPH. The reduction of IDH1 may affect dioxygenase activity and damage the body's detoxification mechanism. Many studies have shown that IDH1 is closely related to the occurrence and development of tumors, and the changes in IDH1 expression levels or gene mutations have appeared in many tumor tissues and produced a series of metabolic and immunity changes at the same time. To better understand the relationship between IDH1 and tumor development, this article reviews the latest advances in IDH1 and tumor metabolism, tumor immunity, IDH1 regulatory mechanisms and IDH1 target inhibitors.
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Affiliation(s)
- Yingqian Ni
- Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan, 250012, China
| | - Peibo Shen
- Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan, 250012, China
| | - Xingchen Wang
- Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan, 250012, China
| | - He Liu
- Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan, 250012, China
| | - Huiyuan Luo
- Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan, 250012, China
| | - Xiuzhen Han
- Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan, 250012, China.,Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Science, Shandong University, China.,Shandong Cancer Hospital and Institute, 440 Jiyan Road, Jinan, 250117, Shandong Province, China
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15
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Heinz A, Nonnenmacher Y, Henne A, Khalil MA, Bejkollari K, Dostert C, Hosseini S, Goldmann O, He W, Palorini R, Verschueren C, Korte M, Chiaradonna F, Medina E, Brenner D, Hiller K. Itaconate controls its own synthesis via feedback-inhibition of reverse TCA cycle activity at IDH2. Biochim Biophys Acta Mol Basis Dis 2022; 1868:166530. [PMID: 36038039 DOI: 10.1016/j.bbadis.2022.166530] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 08/11/2022] [Accepted: 08/17/2022] [Indexed: 11/18/2022]
Abstract
Macrophages undergo extensive metabolic reprogramming during classical pro-inflammatory polarization (M1-like). The accumulation of itaconate has been recognized as both a consequence and mediator of the inflammatory response. In this study we first examined the specific functions of itaconate inside fractionated mitochondria. We show that M1 macrophages produce itaconate de novo via aconitase decarboxylase 1 (ACOD1) inside mitochondria. The carbon for this reaction is not only supplied by oxidative TCA cycling, but also through the reductive carboxylation of α-ketoglutarate by isocitrate dehydrogenase (IDH). While macrophages are capable of sustaining a certain degree of itaconate production during hypoxia by augmenting the activity of IDH-dependent reductive carboxylation, we demonstrate that sufficient itaconate synthesis requires a balance of reductive and oxidative TCA cycle metabolism in mouse macrophages. In comparison, human macrophages increase itaconate accumulation under hypoxic conditions by augmenting reductive carboxylation activity. We further demonstrated that itaconate attenuates reductive carboxylation at IDH2, restricting its own production and the accumulation of the immunomodulatory metabolites citrate and 2-hydroxyglutarate. In line with this, reductive carboxylation is enhanced in ACOD1-depleted macrophages. Mechanistically, the inhibition of IDH2 by itaconate is linked to the alteration of the mitochondrial NADP+/NADPH ratio and competitive succinate dehydrogenase inhibition. Taken together, our findings extend the current model of TCA cycle reprogramming during pro-inflammatory macrophage activation and identified novel regulatory properties of itaconate.
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Affiliation(s)
- Alexander Heinz
- Department for Bioinformatics and Biochemistry, BRICS, Technische Universität Braunschweig, Rebenring 56, 38106 Braunschweig, Germany
| | - Yannic Nonnenmacher
- Department for Bioinformatics and Biochemistry, BRICS, Technische Universität Braunschweig, Rebenring 56, 38106 Braunschweig, Germany
| | - Antonia Henne
- Department for Bioinformatics and Biochemistry, BRICS, Technische Universität Braunschweig, Rebenring 56, 38106 Braunschweig, Germany
| | - Michelle-Amirah Khalil
- Department for Bioinformatics and Biochemistry, BRICS, Technische Universität Braunschweig, Rebenring 56, 38106 Braunschweig, Germany
| | - Ketlin Bejkollari
- Department for Bioinformatics and Biochemistry, BRICS, Technische Universität Braunschweig, Rebenring 56, 38106 Braunschweig, Germany
| | - Catherine Dostert
- Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
| | - Shirin Hosseini
- Department of Cellular Neurobiology, Zoological Institute, Technische Universität Braunschweig, Germany
| | - Oliver Goldmann
- Infection Immunology Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Wei He
- Department for Bioinformatics and Biochemistry, BRICS, Technische Universität Braunschweig, Rebenring 56, 38106 Braunschweig, Germany
| | - Roberta Palorini
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza, Milan, Italy
| | - Charlène Verschueren
- Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
| | - Martin Korte
- Department of Cellular Neurobiology, Zoological Institute, Technische Universität Braunschweig, Germany; Neuroinflammation and Neurodegeneration Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Ferdinando Chiaradonna
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza, Milan, Italy
| | - Eva Medina
- Infection Immunology Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Dirk Brenner
- Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Immunology and Genetics, Luxembourg Centre for System Biomedicine (LCSB), University of Luxembourg, Belval, Luxembourg; Odense Research Center for Anaphylaxis, Department of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, Odense, Denmark
| | - Karsten Hiller
- Department for Bioinformatics and Biochemistry, BRICS, Technische Universität Braunschweig, Rebenring 56, 38106 Braunschweig, Germany.
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16
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Ozgiray E, Sogutlu F, Biray Avci C. Chk1/2 inhibitor AZD7762 enhances the susceptibility of IDH-mutant brain cancer cells to temozolomide. MEDICAL ONCOLOGY (NORTHWOOD, LONDON, ENGLAND) 2022; 39:166. [PMID: 35972603 DOI: 10.1007/s12032-022-01769-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 06/13/2022] [Indexed: 11/28/2022]
Abstract
The IDH mutation initially exhibits chemosensitive properties, progression-free survival cannot be achieved in the later grades, and malignant transformation occurs as a result of TMZ-induced hypermutation profile and adaptation to this profile. In this study, we evaluated the potential of the combination of TMZ and AZD7762 at molecular level, to increase the anticancer activity of TMZ in IDH-mutant U87-mg cells. We used the WST-1 test to evaluate cytotoxic effect of TMZ and AZD7762 combination with dose-effect and isobologram curves. The effects of the inhibitory and effective concentrations of the combination on apoptosis, cell cycle and γ-H2AX phosphorylation were analyzed with flow cytometry. The expression of genes responsible for the DNA damage response was analyzed with qRT-PCR. The combination showed a synergistic effect with high dose reduction index. Single and combined administrations of TMZ and AZD7762 increased in G2/M arrest from 24 to 48 h, and cells in the G2/M phase shifted towards octaploidy at 72 h. While no double-strand breaks were detected after TMZ treatment, AZD7762 and combination treatments caused a significant increase in γ-H2AX phosphorylation and increased apoptotic stimulation towards 72 h although TMZ did not cause apoptotic effect in IDH-mutant U87-mg cells. The genes controlling the apoptosis were determined to be upregulated in all three groups, and genes regarding cell cycle checkpoints were downregulated. Targeting Chk1/2 with AZD7762 simultaneously with TMZ may be a potential therapeutic strategy for both increasing the sensitivity of IDH-mutant glioma cells to TMZ and reducing the dose of TMZ. In IDH-mutant glioma cells, AZD7762, the Chk1/2 inhibitor, can increase the efficacy of Temozolomide by (i) increasing mitotic chaos, and (ii) inhibiting double-strand break repair, (iii) thereby inducing cell death.
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Affiliation(s)
- Erkin Ozgiray
- Department of Neurosurgery, Medicine Faculty, Ege University, Izmir, Turkey
| | - Fatma Sogutlu
- Department of Medical Biology, Medicine Faculty, Ege University, Izmir, Turkey
| | - Cigir Biray Avci
- Department of Medical Biology, Medicine Faculty, Ege University, Izmir, Turkey.
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17
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Genome-Wide Association Study Identifies Multiple Susceptibility Loci for Malignant Neoplasms of the Brain in Taiwan. J Pers Med 2022; 12:jpm12071161. [PMID: 35887658 PMCID: PMC9323978 DOI: 10.3390/jpm12071161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 07/04/2022] [Accepted: 07/14/2022] [Indexed: 11/22/2022] Open
Abstract
Primary brain malignancy is a rare tumor with a global incidence of less than 10 per 100,000 people. Hence, there is limited power for identifying risk loci in individual studies, especially for Han Chinese. We performed a genome-wide association study (GWAS) in Taiwan, including 195 cases and 195 controls. We identified five new genes for malignant neoplasms of the brain: EDARADD (rs645507, 1p31.3, p = 7.71 × 10−5, odds ratio (OR) = 1.893), RBFOX1 (rs8044700, p = 2.35 × 10−5, OR = 2.36), LMF1 (rs3751667, p = 7.24 × 10−7, OR = 2.17), DPP6 (rs67433368, p = 8.32 × 10−5, OR = 3.94), and NDUFB9 (rs7827791, p = 9.73 × 10−6, OR = 4.42). These data support that genetic susceptibility toward GBM or non-GBM tumors is highly distinct, likely reflecting different etiologies. Combined with signaling analysis, we found that RNA modification may be related to major risk factors in primary malignant neoplasms of the brain.
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18
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Chen B, Xiao W, Zou Z, Zhu J, Li D, Yu J, Yang H. Comparing Transcriptomes Reveals Key Metabolic Mechanisms in Superior Growth Performance Nile Tilapia ( Oreochromis niloticus). Front Genet 2022; 13:879570. [PMID: 35903360 PMCID: PMC9322659 DOI: 10.3389/fgene.2022.879570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Accepted: 06/20/2022] [Indexed: 11/23/2022] Open
Abstract
Metabolic capacity is intrinsic to growth performance. To investigate superior growth performance in Nile tilapia, three full-sib families were bred and compared at the biochemical and transcriptome levels to determine metabolic mechanisms involved in significant growth differences between individuals under the same culture environment and feeding regime. Biochemical analysis showed that individuals in the higher growth group had significantly higher total protein, total triglyceride, total cholesterol, and high- and low-density lipoproteins, but significantly lower glucose, as compared with individuals in the lower growth group. Comparative transcriptome analysis showed 536 differentially expressed genes (DEGs) were upregulated, and 622 DEGs were downregulated. These genes were significantly enriched in three key pathways: the tricarboxylic acid cycle (TCA cycle), fatty acid biosynthesis and metabolism, and cholesterol biosynthesis and metabolism. Conjoint analysis of these key pathways and the biochemical parameters suggests that Nile tilapia with superior growth performance have higher ability to consume energy substrates (e.g., glucose), as well as higher ability to biosynthesize fatty acids and cholesterol. Additionally, the fatty acids biosynthesized by the superior growth performance individuals were less active in the catabolic pathway overall, but were more active in the anabolic pathway, and might be used for triglyceride biosynthesis to store excess energy in the form of fat. Furthermore, the tilapia with superior growth performance had lower ability to convert cholesterol into bile acids, but higher ability to convert it into sterols. We discuss the molecular mechanisms of the three key metabolic pathways, map the pathways, and note key factors that may impact the growth of Nile tilapia. The results provide an important guide for the artificial selection and quality enhancement of superior growth performance in tilapia.
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Affiliation(s)
| | | | | | | | | | | | - Hong Yang
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, China
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19
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Gong Y, Wei S, Wei Y, Chen Y, Cui J, Yu Y, Lin X, Yan H, Qin H, Yi L. IDH2: A novel biomarker for environmental exposure in blood circulatory system disorders (Review). Oncol Lett 2022; 24:278. [PMID: 35814829 PMCID: PMC9260733 DOI: 10.3892/ol.2022.13398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 05/24/2022] [Indexed: 11/11/2022] Open
Abstract
As the risk of harmful environmental exposure is increasing, it is important to find suitable targets for the diagnosis and treatment of the diseases caused. Isocitrate dehydrogenase 2 (IDH2) is an enzyme located in the mitochondria; it plays an important role in numerous cell processes, including maintaining redox homeostasis, participating in the tricarboxylic acid cycle and indirectly taking part in the transmission of the oxidative respiratory chain. IDH2 mutations promote progression in acute myeloid leukemia, glioma and other diseases. The present review mainly summarizes the role and mechanism of IDH2 with regard to the biological effects, such as the mitophagy and apoptosis of animal or human cells, caused by environmental pollution such as radiation, heavy metals and other environmental exposure factors. The possible mechanisms of these biological effects are described in terms of IDH2 expression, reduced nicotine adenine dinucleotide phosphate content and reactive oxygen species level, among other variables. The impact of environmental pollution on human health is increasingly attracting attention. IDH2 may therefore become useful as a potential diagnostic and therapeutic target for environmental exposure-induced diseases.
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Affiliation(s)
- Ya Gong
- Institute of Cytology and Genetics, The Hengyang Key Laboratory of Cellular Stress Biology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Shuang Wei
- Institute of Cytology and Genetics, The Hengyang Key Laboratory of Cellular Stress Biology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Yuan Wei
- Institute of Cytology and Genetics, The Hengyang Key Laboratory of Cellular Stress Biology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Yong Chen
- Institute of Cytology and Genetics, The Hengyang Key Laboratory of Cellular Stress Biology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Jian Cui
- Institute of Cardiovascular Disease, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Yue Yu
- Institute of Cytology and Genetics, The Hengyang Key Laboratory of Cellular Stress Biology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Xiang Lin
- Institute of Cytology and Genetics, The Hengyang Key Laboratory of Cellular Stress Biology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Hong Yan
- Pediatric Intensive Care Unit, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Hui Qin
- Institute of Cytology and Genetics, The Hengyang Key Laboratory of Cellular Stress Biology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Lan Yi
- Institute of Cytology and Genetics, The Hengyang Key Laboratory of Cellular Stress Biology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P.R. China
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20
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Zhang H, Puviindran V, Nadesan P, Ding X, Shen L, Tang YJ, Tsushima H, Yahara Y, Ban GI, Zhang GF, Karner CM, Alman BA. Distinct Roles of Glutamine Metabolism in Benign and Malignant Cartilage Tumors With IDH Mutations. J Bone Miner Res 2022; 37:983-996. [PMID: 35220602 PMCID: PMC9314601 DOI: 10.1002/jbmr.4532] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 02/02/2022] [Accepted: 02/21/2022] [Indexed: 12/04/2022]
Abstract
Enchondromas and chondrosarcomas are common cartilage neoplasms that are either benign or malignant, respectively. The majority of these tumors harbor mutations in either IDH1 or IDH2. Glutamine metabolism has been implicated as a critical regulator of tumors with IDH mutations. Using genetic and pharmacological approaches, we demonstrated that glutaminase-mediated glutamine metabolism played distinct roles in enchondromas and chondrosarcomas with IDH1 or IDH2 mutations. Glutamine affected cell differentiation and viability in these tumors differently through different downstream metabolites. During murine enchondroma-like lesion development, glutamine-derived α-ketoglutarate promoted hypertrophic chondrocyte differentiation and regulated chondrocyte proliferation. Deletion of glutaminase in chondrocytes with Idh1 mutation increased the number and size of enchondroma-like lesions. In contrast, pharmacological inhibition of glutaminase in chondrosarcoma xenografts reduced overall tumor burden partially because glutamine-derived non-essential amino acids played an important role in preventing cell apoptosis. This study demonstrates that glutamine metabolism plays different roles in tumor initiation and cancer maintenance. Supplementation of α-ketoglutarate and inhibiting GLS may provide a therapeutic approach to suppress enchondroma and chondrosarcoma tumor growth, respectively. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Hongyuan Zhang
- Department of Cell Biology, Duke University, Durham, NC, USA.,Department of Orthopaedic Surgery, Duke University, Durham, NC, USA
| | | | | | - Xiruo Ding
- Department of Biomedical Informatics and Medical Education, University of Washington, Seattle, WA, USA
| | - Leyao Shen
- Department of Cell Biology, Duke University, Durham, NC, USA.,Department of Orthopaedic Surgery, Duke University, Durham, NC, USA.,Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Yuning J Tang
- Department of Genetics, Stanford University, Stanford, CA, USA
| | | | - Yasuhito Yahara
- Department of Molecular and Medical Pharmacology, Faculty of Medicine, University of Toyama, Toyama, Japan.,Department of Orthopaedic Surgery, Faculty of Medicine, University of Toyama, Toyama, Japan
| | - Ga I Ban
- Department of Orthopaedic Surgery, Duke University, Durham, NC, USA
| | - Guo-Fang Zhang
- Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA.,Department of Medicine, Endocrinology and Metabolism Division, Duke University Medical Center, Durham, NC, USA
| | - Courtney M Karner
- Department of Cell Biology, Duke University, Durham, NC, USA.,Department of Orthopaedic Surgery, Duke University, Durham, NC, USA.,Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Benjamin A Alman
- Department of Cell Biology, Duke University, Durham, NC, USA.,Department of Orthopaedic Surgery, Duke University, Durham, NC, USA
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21
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Draelos MM, Thanapipatsiri A, Du Y, Yokoyama K. Cryptic Phosphorylation-Mediated Divergent Biosynthesis of High-Carbon Sugar Nucleoside Antifungals. ACS Chem Biol 2022; 17:898-907. [PMID: 35348322 DOI: 10.1021/acschembio.1c00971] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Establishing a general biosynthetic scheme for natural products is critical for a broader understanding of natural product biosynthesis and the structural prediction of metabolites based on genome sequence information. High-carbon sugar nucleoside antimicrobials are an underexplored class of natural products with unique structures and important biological activities. Recent studies on C6 sugar nucleoside antifungal natural products, such as nikkomycins and polyoxins, revealed a novel biosynthetic mechanism involving cryptic phosphorylation. However, the generality of this biosynthetic mechanism remained unexplored. We here report in vitro characterization of the biosynthesis of a C7 sugar nucleoside antifungal, malayamycin A. Our results demonstrate that the malayamycin biosynthetic enzymes specifically accept 2'-phosphorylated biosynthetic intermediates, suggesting that cryptic phosphorylation-mediated biosynthesis is conserved beyond C6 sugar nucleosides. Furthermore, the results suggest a generalizable divergent biosynthetic mechanism for high-carbon sugar nucleoside antifungals. In this model, C6 and C7 sugar nucleoside biosyntheses proceed via a common C8 sugar nucleoside precursor, and the sugar size is determined using the functions of α-ketoglutarate (α-KG)-dependent dioxygenases (NikI/PolD for C6 sugar nucleosides and MalI for C7 sugar nucleosides). These results provide an important guidance for the future genome-mining discovery of high-carbon sugar nucleoside antimicrobials.
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Affiliation(s)
- Matthew M. Draelos
- Department of Chemistry, Duke University, Durham, North Carolina 27710, United States
| | - Anyarat Thanapipatsiri
- Department of Biochemistry, Duke University, Durham, North Carolina 27710, United States
| | - Yanan Du
- Department of Biochemistry, Duke University, Durham, North Carolina 27710, United States
| | - Kenichi Yokoyama
- Department of Chemistry, Duke University, Durham, North Carolina 27710, United States
- Department of Biochemistry, Duke University, Durham, North Carolina 27710, United States
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22
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Mazurek M, Szczepanek D, Orzyłowska A, Rola R. Analysis of Factors Affecting 5-ALA Fluorescence Intensity in Visualizing Glial Tumor Cells-Literature Review. Int J Mol Sci 2022; 23:ijms23020926. [PMID: 35055109 PMCID: PMC8779265 DOI: 10.3390/ijms23020926] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 01/11/2022] [Accepted: 01/13/2022] [Indexed: 01/27/2023] Open
Abstract
Glial tumors are one of the most common lesions of the central nervous system. Despite the implementation of appropriate treatment, the prognosis is not successful. As shown in the literature, maximal tumor resection is a key element in improving therapeutic outcome. One of the methods to achieve it is the use of fluorescent intraoperative navigation with 5-aminolevulinic acid. Unfortunately, often the level of fluorescence emitted is not satisfactory, resulting in difficulties in the course of surgery. This article summarizes currently available knowledge regarding differences in the level of emitted fluorescence. It may depend on both the histological type and the genetic profile of the tumor, which is reflected in the activity and expression of enzymes involved in the intracellular metabolism of fluorescent dyes, such as PBGD, FECH, UROS, and ALAS. The transport of 5-aminolevulinic acid and its metabolites across the blood–brain barrier and cell membranes mediated by transporters, such as ABCB6 and ABCG2, is also important. Accompanying therapies, such as antiepileptic drugs or steroids, also have an impact on light emission by tumor cells. Accurate determination of the factors influencing the fluorescence of 5-aminolevulinic acid-treated cells may contribute to the improvement of fluorescence navigation in patients with highly malignant gliomas.
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23
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Alzial G, Renoult O, Paris F, Gratas C, Clavreul A, Pecqueur C. Wild-type isocitrate dehydrogenase under the spotlight in glioblastoma. Oncogene 2022; 41:613-621. [PMID: 34764443 PMCID: PMC8799461 DOI: 10.1038/s41388-021-02056-1] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 09/21/2021] [Accepted: 09/30/2021] [Indexed: 01/03/2023]
Abstract
Brain tumors actively reprogram their cellular metabolism to survive and proliferate, thus offering potential therapeutic opportunities. Over the past decade, extensive research has been done on mutant IDH enzymes as markers of good prognosis in glioblastoma, a highly aggressive brain tumor in adults with dismal prognosis. Yet, 95% of glioblastoma are IDH wild-type. Here, we review current knowledge about IDH wild-type enzymes and their putative role in mechanisms driving tumor progression. After a brief overview on tumor metabolic adaptation, we present the diverse metabolic function of IDH enzymes and their roles in glioblastoma initiation, progression and response to treatments. Finally, we will discuss wild-type IDH targeting in primary glioblastoma.
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Affiliation(s)
- Gabriel Alzial
- Université de Nantes, CRCINA, INSERM, CNRS, F-44000, Nantes, France
| | - Ophelie Renoult
- Université de Nantes, CRCINA, INSERM, CNRS, F-44000, Nantes, France
| | - François Paris
- Université de Nantes, CRCINA, INSERM, CNRS, F-44000, Nantes, France
- Institut de Cancérologie de l'Ouest, Saint-Herblain, France
| | - Catherine Gratas
- Université de Nantes, CHU Nantes, Inserm, CRCINA, F-44000, Nantes, France
| | - Anne Clavreul
- Université d'Angers, CHU d'Angers, CRCINA, F-49000, Angers, France
- Département de Neurochirurgie, CHU Angers, Angers, France
| | - Claire Pecqueur
- Université de Nantes, CRCINA, INSERM, CNRS, F-44000, Nantes, France.
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24
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Gritsch S, Batchelor TT, Gonzalez Castro LN. Diagnostic, therapeutic, and prognostic implications of the 2021 World Health Organization classification of tumors of the central nervous system. Cancer 2022; 128:47-58. [PMID: 34633681 DOI: 10.1002/cncr.33918] [Citation(s) in RCA: 160] [Impact Index Per Article: 53.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 08/16/2021] [Accepted: 08/17/2021] [Indexed: 12/17/2022]
Abstract
The 2016 revised fourth edition of the World Health Organization (WHO) classification of central nervous system (CNS) tumors incorporated molecular features with histologic grading, revolutionizing how oncologists conceptualize primary brain and spinal cord tumors as well as providing new insights into their management and prognosis. The 2021 revised fifth edition of the WHO classification further integrates molecular alterations for CNS tumor categorization, updating current understanding of the pathophysiology of many of these disease entities. Here, the authors review changes in the new classification for the most common primary adult tumors-gliomas (including astrocytomas, oligodendrogliomas, and ependymomas) and meningiomas-highlighting the key genomic alterations for each group classification to help clinicians interpret them as they consider therapeutic options-including clinical trials and targeted therapies-and discuss the prognosis of these tumors with their patients. The revised, updated 2021 WHO classification also further integrates molecular alterations in the classification of pediatric CNS tumors, but those are not covered in the current review.
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Affiliation(s)
- Simon Gritsch
- Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Tracy T Batchelor
- Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
- Center for Neuro-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - L Nicolas Gonzalez Castro
- Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
- Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
- Center for Neuro-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
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25
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Hvinden IC, Cadoux-Hudson T, Schofield CJ, McCullagh JS. Metabolic adaptations in cancers expressing isocitrate dehydrogenase mutations. Cell Rep Med 2021; 2:100469. [PMID: 35028610 PMCID: PMC8714851 DOI: 10.1016/j.xcrm.2021.100469] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
The most frequently mutated metabolic genes in human cancer are those encoding the enzymes isocitrate dehydrogenase 1 (IDH1) and IDH2; these mutations have so far been identified in more than 20 tumor types. Since IDH mutations were first reported in glioma over a decade ago, extensive research has revealed their association with altered cellular processes. Mutations in IDH lead to a change in enzyme function, enabling efficient conversion of 2-oxoglutarate to R-2-hydroxyglutarate (R-2-HG). It is proposed that elevated cellular R-2-HG inhibits enzymes that regulate transcription and metabolism, subsequently affecting nuclear, cytoplasmic, and mitochondrial biochemistry. The significance of these biochemical changes for tumorigenesis and potential for therapeutic exploitation remains unclear. Here we comprehensively review reported direct and indirect metabolic changes linked to IDH mutations and discuss their clinical significance. We also review the metabolic effects of first-generation mutant IDH inhibitors and highlight the potential for combination treatment strategies and new metabolic targets.
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Affiliation(s)
- Ingvild Comfort Hvinden
- Chemistry Research Laboratory, 12 Mansfield Road, Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK
| | - Tom Cadoux-Hudson
- Chemistry Research Laboratory, 12 Mansfield Road, Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK
| | - Christopher J. Schofield
- Chemistry Research Laboratory, 12 Mansfield Road, Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK
- Ineos Oxford Institute for Antimicrobial Research, 12 Mansfield Road, Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK
| | - James S.O. McCullagh
- Chemistry Research Laboratory, 12 Mansfield Road, Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK
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26
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Cadoux-Hudson T, Schofield CJ, McCullagh JS. Isocitrate dehydrogenase gene variants in cancer and their clinical significance. Biochem Soc Trans 2021; 49:2561-2572. [PMID: 34854890 PMCID: PMC8786286 DOI: 10.1042/bst20210277] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 10/13/2021] [Accepted: 10/18/2021] [Indexed: 11/30/2022]
Abstract
Human isocitrate dehydrogenase (IDH) genes encode for the IDH1, 2 & 3 isoenzymes which catalyse the formation of 2-oxoglutarate from isocitrate and are essential for normal mammalian metabolism. Although mutations in these genes in cancer were long thought to lead to a 'loss of function', combined genomic and metabolomic studies led to the discovery that a common IDH 1 mutation, present in low-grade glioma and acute myeloid leukaemia (AML), yields a variant (R132H) with a striking change of function leading to the production of (2R)-hydroxyglutarate (2HG) which consequently accumulates in large quantities both within and outside cells. Elevated 2HG is proposed to promote tumorigenesis, although the precise mechanism by which it does this remains uncertain. Inhibitors of R132H IDH1, and other subsequently identified cancer-linked 2HG producing IDH variants, are approved for clinical use in the treatment of chemotherapy-resistant AML, though resistance enabled by additional substitutions has emerged. In this review, we provide a current overview of cancer linked IDH mutations focussing on their distribution in different cancer types, the effects of substitution mutations on enzyme activity, the mode of action of recently developed inhibitors, and their relationship with emerging resistance-mediating double mutations.
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Affiliation(s)
- Thomas Cadoux-Hudson
- Chemistry Research Laboratory, Department of Chemistry and the Ineos Institute for Antimicrobial Research, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K
| | - Christopher J. Schofield
- Chemistry Research Laboratory, Department of Chemistry and the Ineos Institute for Antimicrobial Research, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K
| | - James S.O. McCullagh
- Chemistry Research Laboratory, Department of Chemistry and the Ineos Institute for Antimicrobial Research, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K
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27
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Herold RA, Reinbold R, Megarity CF, Abboud MI, Schofield CJ, Armstrong FA. Exploiting Electrode Nanoconfinement to Investigate the Catalytic Properties of Isocitrate Dehydrogenase (IDH1) and a Cancer-Associated Variant. J Phys Chem Lett 2021; 12:6095-6101. [PMID: 34170697 PMCID: PMC8273889 DOI: 10.1021/acs.jpclett.1c01517] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 06/22/2021] [Indexed: 06/13/2023]
Abstract
Human isocitrate dehydrogenase (IDH1) and its cancer-associated variant (IDH1 R132H) are rendered electroactive through coconfinement with a rapid NADP(H) recycling enzyme (ferredoxin-NADP+ reductase) in nanopores formed within an indium tin oxide electrode. Efficient coupling to localized NADP(H) enables IDH activity to be energized, controlled, and monitored in real time, leading directly to a thermodynamic redox landscape for accumulation of the oncometabolite, 2-hydroxyglutarate, that would occur in biological environments when the R132H variant is present. The technique enables time-resolved, in situ measurements of the kinetics of binding and dissociation of inhibitory drugs.
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28
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Sesanto R, Kuehn JF, Barber DL, White KA. Low pH Facilitates Heterodimerization of Mutant Isocitrate Dehydrogenase IDH1-R132H and Promotes Production of 2-Hydroxyglutarate. Biochemistry 2021; 60:1983-1994. [PMID: 34143606 PMCID: PMC8246651 DOI: 10.1021/acs.biochem.1c00059] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
![]()
Isocitrate dehydrogenase
1 (IDH1) is a key metabolic enzyme for
maintaining cytosolic levels of α-ketoglutarate (AKG) and preserving
the redox environment of the cytosol. Wild-type (WT) IDH1 converts
isocitrate to AKG; however, mutant IDH1-R132H that is recurrent in
human cancers catalyzes the neomorphic production of the oncometabolite d-2-hydroxyglutrate (D-2HG) from AKG. Recent work suggests that
production of l-2-hydroxyglutarte in cancer cells can be
regulated by environmental changes, including hypoxia and intracellular
pH (pHi). However, it is unknown whether and how pHi affects the activity
of IDH1-R132H. Here, we show that in cells IDH1-R132H can produce
D-2HG in a pH-dependent manner with increased production at lower
pHi. We also identify a molecular mechanism by which this pH sensitivity
is achieved. We show that pH-dependent production of D-2HG is mediated
by pH-dependent heterodimer formation between IDH1-WT and IDH1-R132H.
In contrast, neither IDH1-WT nor IDH1-R132H homodimer formation is
affected by pH. Our results demonstrate that robust production of
D-2HG by IDH1-R132H relies on the coincidence of (1) the ability to
form heterodimers with IDH1-WT and (2) low pHi or highly abundant
AKG substrate. These data suggest cancer-associated IDH1-R132H may
be sensitive to physiological or microenvironmental cues that lower
pH, such as hypoxia or metabolic reprogramming. This work reveals
new molecular considerations for targeted therapeutics and suggests
potential synergistic effects of using catalytic IDH1 inhibitors targeting
D-2HG production in combination with drugs targeting the tumor microenvironment.
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Affiliation(s)
- Rae Sesanto
- Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, California 94122, United States
| | - Jessamine F Kuehn
- Department of Chemistry and Biochemistry, The University of Notre Dame, Notre Dame, Indiana 46556, United States.,Harper Cancer Research Institute, South Bend, Indiana 46617, United States
| | - Diane L Barber
- Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, California 94122, United States
| | - Katharine A White
- Department of Chemistry and Biochemistry, The University of Notre Dame, Notre Dame, Indiana 46556, United States.,Harper Cancer Research Institute, South Bend, Indiana 46617, United States
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29
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Abstract
PURPOSE OF REVIEW Enchondroma is a common cartilage benign tumor that develops from dysregulation of chondrocyte terminal differentiation during growth plate development. Here we provide an overview of recent progress in understanding causative mutations for enchondroma, dysregulated signaling and metabolic pathways in enchondroma, and the progression from enchondroma to malignant chondrosarcoma. RECENT FINDINGS Several signaling pathways that regulate chondrocyte differentiation are dysregulated in enchondromas. Somatic mutations in the metabolic enzymes isocitrate dehydrogenase 1 and 2 (IDH1/2) are the most common findings in enchondromas. Mechanisms including metabolic regulation, epigenetic regulation, and altered signaling pathways play a role in enchondroma formation and progression. Multiple pathways regulate growth plate development in a coordinated manner. Deregulation of the process can result in chondrocytes failing to undergo differentiation and the development of enchondroma.
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Affiliation(s)
- Hongyuan Zhang
- Department of Orthopaedic Surgery, Duke University School of Medicine, Durham, NC, 27710, USA
- Department of Cell Biology, Duke University School of Medicine, Durham, NC, 27710, USA
| | - Benjamin A Alman
- Department of Orthopaedic Surgery, Duke University School of Medicine, Durham, NC, 27710, USA.
- Department of Cell Biology, Duke University School of Medicine, Durham, NC, 27710, USA.
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30
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An acidic residue buried in the dimer interface of isocitrate dehydrogenase 1 (IDH1) helps regulate catalysis and pH sensitivity. Biochem J 2021; 477:2999-3018. [PMID: 32729927 DOI: 10.1042/bcj20200311] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 07/28/2020] [Accepted: 07/29/2020] [Indexed: 12/19/2022]
Abstract
Isocitrate dehydrogenase 1 (IDH1) catalyzes the reversible NADP+-dependent conversion of isocitrate to α-ketoglutarate (αKG) to provide critical cytosolic substrates and drive NADPH-dependent reactions like lipid biosynthesis and glutathione regeneration. In biochemical studies, the forward reaction is studied at neutral pH, while the reverse reaction is typically characterized in more acidic buffers. This led us to question whether IDH1 catalysis is pH-regulated, which would have functional implications under conditions that alter cellular pH, like apoptosis, hypoxia, cancer, and neurodegenerative diseases. Here, we show evidence of catalytic regulation of IDH1 by pH, identifying a trend of increasing kcat values for αKG production upon increasing pH in the buffers we tested. To understand the molecular determinants of IDH1 pH sensitivity, we used the pHinder algorithm to identify buried ionizable residues predicted to have shifted pKa values. Such residues can serve as pH sensors, with changes in protonation states leading to conformational changes that regulate catalysis. We identified an acidic residue buried at the IDH1 dimer interface, D273, with a predicted pKa value upshifted into the physiological range. D273 point mutations had decreased catalytic efficiency and, importantly, loss of pH-regulated catalysis. Based on these findings, we conclude that IDH1 activity is regulated, at least in part, by pH. We show this regulation is mediated by at least one buried acidic residue ∼12 Å from the IDH1 active site. By establishing mechanisms of regulation of this well-conserved enzyme, we highlight catalytic features that may be susceptible to pH changes caused by cell stress and disease.
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31
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Lita A, Pliss A, Kuzmin A, Yamasaki T, Zhang L, Dowdy T, Burks C, de Val N, Celiku O, Ruiz-Rodado V, Nicoli ER, Kruhlak M, Andresson T, Das S, Yang C, Schmitt R, Herold-Mende C, Gilbert MR, Prasad PN, Larion M. IDH1 mutations induce organelle defects via dysregulated phospholipids. Nat Commun 2021; 12:614. [PMID: 33504762 PMCID: PMC7840755 DOI: 10.1038/s41467-020-20752-6] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Accepted: 12/11/2020] [Indexed: 01/25/2023] Open
Abstract
Infiltrating gliomas are devastating and incurable tumors. Amongst all gliomas, those harboring a mutation in isocitrate dehydrogenase 1 mutation (IDH1mut) acquire a different tumor biology and clinical manifestation from those that are IDH1WT. Understanding the unique metabolic profile reprogrammed by IDH1 mutation has the potential to identify new molecular targets for glioma therapy. Herein, we uncover increased monounsaturated fatty acids (MUFA) and their phospholipids in endoplasmic reticulum (ER), generated by IDH1 mutation, that are responsible for Golgi and ER dilation. We demonstrate a direct link between the IDH1 mutation and this organelle morphology via D-2HG-induced stearyl-CoA desaturase (SCD) overexpression, the rate-limiting enzyme in MUFA biosynthesis. Inhibition of IDH1 mutation or SCD silencing restores ER and Golgi morphology, while D-2HG and oleic acid induces morphological defects in these organelles. Moreover, addition of oleic acid, which tilts the balance towards elevated levels of MUFA, produces IDH1mut-specific cellular apoptosis. Collectively, these results suggest that IDH1mut-induced SCD overexpression can rearrange the distribution of lipids in the organelles of glioma cells, providing new insight into the link between lipid metabolism and organelle morphology in these cells, with potential and unique therapeutic implications.
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Affiliation(s)
- Adrian Lita
- Neuro-Oncology Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, MD, USA
| | - Artem Pliss
- Institute for Lasers, Photonics and Biophotonics, University at Buffalo, State University of New York, Buffalo, NY, 14260, USA
| | - Andrey Kuzmin
- Institute for Lasers, Photonics and Biophotonics, University at Buffalo, State University of New York, Buffalo, NY, 14260, USA
- Advanced Cytometry Instrumentation Systems, LLC, Buffalo, NY, 14260, USA
| | - Tomohiro Yamasaki
- Neuro-Oncology Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, MD, USA
| | - Lumin Zhang
- Neuro-Oncology Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, MD, USA
| | - Tyrone Dowdy
- Neuro-Oncology Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, MD, USA
| | - Christina Burks
- Electron Microscopy Laboratory, Frederick National Laboratory for Cancer Research, Center for Cancer Research, National Cancer Institute, Frederick, MD, 21702, USA
| | - Natalia de Val
- Electron Microscopy Laboratory, Frederick National Laboratory for Cancer Research, Center for Cancer Research, National Cancer Institute, Frederick, MD, 21702, USA
- Center for Molecular Microscopy, Center for Cancer Research, National Cancer Institute, Frederick, MD, 21702, USA
- Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, 21701, USA
| | - Orieta Celiku
- Neuro-Oncology Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, MD, USA
| | - Victor Ruiz-Rodado
- Neuro-Oncology Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, MD, USA
| | - Elena-Raluca Nicoli
- Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD, 20892, USA
| | - Michael Kruhlak
- Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD, 20892, USA
| | - Thorkell Andresson
- Protein Characterization Laboratory of the Cancer Research Technology Program (CRTP), National Cancer Institute, Frederick, MD, 21702, USA
| | - Sudipto Das
- Protein Characterization Laboratory of the Cancer Research Technology Program (CRTP), National Cancer Institute, Frederick, MD, 21702, USA
| | - Chunzhang Yang
- Neuro-Oncology Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, MD, USA
| | - Rebecca Schmitt
- Institute for Lasers, Photonics and Biophotonics, University at Buffalo, State University of New York, Buffalo, NY, 14260, USA
| | - Christel Herold-Mende
- Division of Neurosurgical Research, Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Mark R Gilbert
- Neuro-Oncology Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, MD, USA
| | - Paras N Prasad
- Institute for Lasers, Photonics and Biophotonics, University at Buffalo, State University of New York, Buffalo, NY, 14260, USA
- Advanced Cytometry Instrumentation Systems, LLC, Buffalo, NY, 14260, USA
| | - Mioara Larion
- Neuro-Oncology Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, MD, USA.
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32
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Borst P. The malate-aspartate shuttle (Borst cycle): How it started and developed into a major metabolic pathway. IUBMB Life 2020; 72:2241-2259. [PMID: 32916028 PMCID: PMC7693074 DOI: 10.1002/iub.2367] [Citation(s) in RCA: 133] [Impact Index Per Article: 26.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 07/29/2020] [Indexed: 12/20/2022]
Abstract
This article presents a personal and critical review of the history of the malate-aspartate shuttle (MAS), starting in 1962 and ending in 2020. The MAS was initially proposed as a route for the oxidation of cytosolic NADH by the mitochondria in Ehrlich ascites cell tumor lacking other routes, and to explain the need for a mitochondrial aspartate aminotransferase (glutamate oxaloacetate transaminase 2 [GOT2]). The MAS was soon adopted in the field as a major pathway for NADH oxidation in mammalian tissues, such as liver and heart, even though the energetics of the MAS remained a mystery. Only in the 1970s, LaNoue and coworkers discovered that the efflux of aspartate from mitochondria, an essential step in the MAS, is dependent on the proton-motive force generated by the respiratory chain: for every aspartate effluxed, mitochondria take up one glutamate and one proton. This makes the MAS in practice uni-directional toward oxidation of cytosolic NADH, and explains why the free NADH/NAD ratio is much higher in the mitochondria than in the cytosol. The MAS is still a very active field of research. Most recently, the focus has been on the role of the MAS in tumors, on cells with defects in mitochondria and on inborn errors in the MAS. The year 2019 saw the discovery of two new inborn errors in the MAS, deficiencies in malate dehydrogenase 1 and in aspartate transaminase 2 (GOT2). This illustrates the vitality of ongoing MAS research.
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Affiliation(s)
- Piet Borst
- Division of Cell BiologyThe Netherlands Cancer InstituteAmsterdamThe Netherlands
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33
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Sepulveda-Villegas M, Rojo R, Garza-Hernandez D, de la Rosa-Garza M, Treviño V. A systematic review of genes affecting mitochondrial processes in cancer. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165846. [PMID: 32473387 DOI: 10.1016/j.bbadis.2020.165846] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 05/01/2020] [Accepted: 05/21/2020] [Indexed: 02/07/2023]
Abstract
Malignant conversion of cancer cells requires efficient mitochondria reprogramming orchestrated by hundreds of genes. The transformation includes increased energy demand, biosynthesis of precursors, and reactive oxygen species needed to accelerate cell growth, proliferation, and survival. Reprogramming involves complex gene alterations that have not been methodically curated. Therefore, we systematically analyzed the literature of cancer-related genes in mitochondria. Through the analysis of >2500 PubMed abstracts and >1600 human genes, we identified 228 genes showing clear roles in cancer. Each gene was classified according to their homeostatic function, together with the pathological transitions that contribute to specific cancer hallmarks. The potential clinical relevance of these hallmarks and genes is discussed by representative examples and validated by detecting differences in gene expression levels across 16 different types of cancer. A compendium, including the gene functions and alterations underpinning cancer progression, can be explored at http://bioinformatica.mty.itesm.mx/MitoCancer.
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Affiliation(s)
- Maricruz Sepulveda-Villegas
- Tecnologico de Monterrey, Escuela de Medicina, Cátedra de Bioinformática, Av. Morones Prieto No. 3000, Colonia Los Doctores, Monterrey, Nuevo León 64710, Mexico
| | - Rocio Rojo
- Tecnologico de Monterrey, Escuela de Medicina, Cátedra de Bioinformática, Av. Morones Prieto No. 3000, Colonia Los Doctores, Monterrey, Nuevo León 64710, Mexico
| | - Debora Garza-Hernandez
- Tecnologico de Monterrey, Escuela de Medicina, Cátedra de Bioinformática, Av. Morones Prieto No. 3000, Colonia Los Doctores, Monterrey, Nuevo León 64710, Mexico
| | - Mauricio de la Rosa-Garza
- Tecnologico de Monterrey, Escuela de Medicina, Cátedra de Bioinformática, Av. Morones Prieto No. 3000, Colonia Los Doctores, Monterrey, Nuevo León 64710, Mexico
| | - Victor Treviño
- Tecnologico de Monterrey, Escuela de Medicina, Cátedra de Bioinformática, Av. Morones Prieto No. 3000, Colonia Los Doctores, Monterrey, Nuevo León 64710, Mexico.
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34
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Chiral discrimination in a mutated IDH enzymatic reaction in cancer: a computational perspective. EUROPEAN BIOPHYSICS JOURNAL: EBJ 2020; 49:549-559. [PMID: 32880665 DOI: 10.1007/s00249-020-01460-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 08/24/2020] [Indexed: 10/23/2022]
Abstract
Chiral discrimination in biological systems, such as L-amino acids in proteins and d-sugars in nucleic acids, has been proposed to depend on various mechanisms, and chiral discrimination by mutated enzymes mediating cancer cell signaling is important in current research. We have explored how mutated isocitrate dehydrogenase (IDH) catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate which in turn is converted to d-2-hydroxyglutatrate (d-2HG) as a preferred product instead of l-2-hydroxyglutatrate (l-2HG) according to quantum chemical calculations. Using transition state structure modeling, we delineate the preferred product formation of d-2HG over l-2HG in an IDH active site model. The mechanisms for the formation of d-2HG over l-2HG are assessed by identifying transition state structures and activation energy barriers in gas and solution phases. The calculated reaction energy profile for the formation of d-2HG and l-2HG metabolites shows a 29 times higher value for l-2HG as compared to d-2HG. Results for second-order Møller-Plesset perturbation theory (MP2) do not alter the observed trend based on Density Functional Theory (DFT). The observed trends in reaction energy profile explain why the formation of D-2HG is preferred over l-2HG and reveal why mutation leads to the formation of d-2HG instead of l-2HG. For a better understanding of the observed difference in the activation barrier for the formation of the two alternative products, we performed natural bond orbital analysis, non-covalent interactions analysis and energy decomposition analysis. Our findings based on computational calculations clearly indicate a role for chiral discrimination in mutated enzymatic pathways in cancer biology.
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Isocitrate dehydrogenase 1 mutation enhances 24(S)-hydroxycholesterol production and alters cholesterol homeostasis in glioma. Oncogene 2020; 39:6340-6353. [PMID: 32855525 DOI: 10.1038/s41388-020-01439-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 08/10/2020] [Accepted: 08/17/2020] [Indexed: 01/08/2023]
Abstract
Isocitrate dehydrogenase (IDH) mutation is the most important initiating event in gliomagenesis, and the increasing evidence shows that IDH mutation is associated with the metabolic reprogramming in the tumor. Dysregulated cholesterol metabolism is a hallmark of tumor cells, but the cholesterol homeostasis in IDH-mutated glioma is still unknown. In this study, we found that astrocyte-specific mutant IDH1(R132H) knockin reduced the cholesterol contents and damaged the structure of myelin in mouse brains. In U87 and U251 cells, the expression of mutant IDH1 consistently reduced the cholesterol levels. Furthermore, we found that IDH1 mutation enhanced the production of 24(S)-hydroxycholesterol (24-OHC), which is not only the metabolite of cholesterol elimination, but also functions as an endogenous ligand for the liver X receptors (LXRs). In IDH1-mutant glioma cells, the elevated 24-OHC activated LXRs, which consequently accelerated the low-density lipoprotein receptor (LDLR) degradation by upregulating the inducible degrader of the LDLR (IDOL). The reduced LDLR expressions in IDH1-mutant glioma cells abated the uptakes of low-density lipoprotein (LDL) to decrease the cholesterol influx. In addition, the activated LXRs also promoted the cholesterol efflux by elevating the ATP-binding cassette transporter A1 (ABCA1), ABCG1, and apolipoprotein E (ApoE) in both IDH1-mutant astrocytes and glioma cells. As a feedback, the reduced cholesterol levels stimulated the cholesterol biosynthesis, which made IDH1-mutated glioma cells more sensitive to atorvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase. The altered cholesterol homeostasis regulated by mutant IDH provides a pivotal therapeutical strategy for the IDH-mutated gliomas.
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Ferreri C, Sansone A, Ferreri R, Amézaga J, Tueros I. Fatty Acids and Membrane Lipidomics in Oncology: A Cross-Road of Nutritional, Signaling and Metabolic Pathways. Metabolites 2020; 10:metabo10090345. [PMID: 32854444 PMCID: PMC7570129 DOI: 10.3390/metabo10090345] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 08/20/2020] [Accepted: 08/23/2020] [Indexed: 12/11/2022] Open
Abstract
Fatty acids are closely involved in lipid synthesis and metabolism in cancer. Their amount and composition are dependent on dietary supply and tumor microenviroment. Research in this subject highlighted the crucial event of membrane formation, which is regulated by the fatty acids' molecular properties. The growing understanding of the pathways that create the fatty acid pool needed for cell replication is the result of lipidomics studies, also envisaging novel fatty acid biosynthesis and fatty acid-mediated signaling. Fatty acid-driven mechanisms and biological effects in cancer onset, growth and metastasis have been elucidated, recognizing the importance of polyunsaturated molecules and the balance between omega-6 and omega-3 families. Saturated and monounsaturated fatty acids are biomarkers in several types of cancer, and their characterization in cell membranes and exosomes is under development for diagnostic purposes. Desaturase enzymatic activity with unprecedented de novo polyunsaturated fatty acid (PUFA) synthesis is considered the recent breakthrough in this scenario. Together with the link between obesity and cancer, fatty acids open interesting perspectives for biomarker discovery and nutritional strategies to control cancer, also in combination with therapies. All these subjects are described using an integrated approach taking into account biochemical, biological and analytical aspects, delineating innovations in cancer prevention, diagnostics and treatments.
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Affiliation(s)
- Carla Ferreri
- Istituto per la Sintesi Organica e la Fotoreattività, Consiglio Nazionale delle Ricerche, Via Piero Gobetti 101, 40129 Bologna, Italy;
- Correspondence:
| | - Anna Sansone
- Istituto per la Sintesi Organica e la Fotoreattività, Consiglio Nazionale delle Ricerche, Via Piero Gobetti 101, 40129 Bologna, Italy;
| | - Rosaria Ferreri
- Department of Integrated Medicine, Tuscany Reference Centre for Integrated Medicine in the hospital pathway, Pitigliano Hospital, Via Nicola Ciacci, 340, 58017 Pitigliano, Italy;
| | - Javier Amézaga
- AZTI, Food and Health, Parque Tecnológico de Bizkaia, Astondo Bidea, Edificio 609, 48160 Derio, Spain; (J.A.); (I.T.)
| | - Itziar Tueros
- AZTI, Food and Health, Parque Tecnológico de Bizkaia, Astondo Bidea, Edificio 609, 48160 Derio, Spain; (J.A.); (I.T.)
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Liu L, Lu JY, Li F, Xing X, Li T, Yang X, Shen X. IDH1 fine-tunes cap-dependent translation initiation. J Mol Cell Biol 2020; 11:816-828. [PMID: 31408165 PMCID: PMC6884706 DOI: 10.1093/jmcb/mjz082] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Revised: 06/02/2019] [Accepted: 06/18/2019] [Indexed: 12/15/2022] Open
Abstract
The metabolic enzyme isocitrate dehydrogenase 1 (IDH1) catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG). Its mutation often leads to aberrant gene expression in cancer. IDH1 was reported to bind thousands of RNA transcripts in a sequence-dependent manner; yet, the functional significance of this RNA-binding activity remains elusive. Here, we report that IDH1 promotes mRNA translation via direct associations with polysome mRNA and translation machinery. Comprehensive proteomic analysis in embryonic stem cells (ESCs) revealed striking enrichment of ribosomal proteins and translation regulators in IDH1-bound protein interactomes. We performed ribosomal profiling and analyzed mRNA transcripts that are associated with actively translating polysomes. Interestingly, knockout of IDH1 in ESCs led to significant downregulation of polysome-bound mRNA in IDH1 targets and subtle upregulation of ribosome densities at the start codon, indicating inefficient translation initiation upon loss of IDH1. Tethering IDH1 to a luciferase mRNA via the MS2-MBP system promotes luciferase translation, independently of the catalytic activity of IDH1. Intriguingly, IDH1 fails to enhance luciferase translation driven by an internal ribosome entry site. Together, these results reveal an unforeseen role of IDH1 in fine-tuning cap-dependent translation via the initiation step.
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Affiliation(s)
- Lichao Liu
- Tsinghua-Peking Center for Life Sciences, School of Medicine and School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - J Yuyang Lu
- Tsinghua-Peking Center for Life Sciences, School of Medicine and School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Fajin Li
- MOE Key Laboratory of Bioinformatics, Center for Synthetic & Systems Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Xudong Xing
- Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Tong Li
- Tsinghua-Peking Center for Life Sciences, School of Medicine and School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Xuerui Yang
- MOE Key Laboratory of Bioinformatics, Center for Synthetic & Systems Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Xiaohua Shen
- Tsinghua-Peking Center for Life Sciences, School of Medicine and School of Life Sciences, Tsinghua University, Beijing 100084, China
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Smolková K, Špačková J, Gotvaldová K, Dvořák A, Křenková A, Hubálek M, Holendová B, Vítek L, Ježek P. SIRT3 and GCN5L regulation of NADP+- and NADPH-driven reactions of mitochondrial isocitrate dehydrogenase IDH2. Sci Rep 2020; 10:8677. [PMID: 32457458 PMCID: PMC7250847 DOI: 10.1038/s41598-020-65351-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 04/29/2020] [Indexed: 12/22/2022] Open
Abstract
Wild type mitochondrial isocitrate dehydrogenase (IDH2) was previously reported to produce oncometabolite 2-hydroxyglutarate (2HG). Besides, mitochondrial deacetylase SIRT3 has been shown to regulate the oxidative function of IDH2. However, regulation of 2HG formation by SIRT3-mediated deacetylation was not investigated yet. We aimed to study mitochondrial IDH2 function in response to acetylation and deacetylation, and focus specifically on 2HG production by IDH2. We used acetylation surrogate mutant of IDH2 K413Q and assayed enzyme kinetics of oxidative decarboxylation of isocitrate, 2HG production by the enzyme, and 2HG production in cells. The purified IDH2 K413Q exhibited lower oxidative reaction rates than IDH2 WT. 2HG production by IDH2 K413Q was largely diminished at the enzymatic and cellular level, and knockdown of SIRT3 also inhibited 2HG production by IDH2. Contrary, the expression of putative mitochondrial acetylase GCN5L likely does not target IDH2. Using mass spectroscopy, we further identified lysine residues within IDH2, which are the substrates of SIRT3. In summary, we demonstrate that 2HG levels arise from non-mutant IDH2 reductive function and decrease with increasing acetylation level. The newly identified lysine residues might apply in regulation of IDH2 function in response to metabolic perturbations occurring in cancer cells, such as glucose-free conditions.
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Affiliation(s)
- Katarína Smolková
- Laboratory of Mitochondrial Physiology, No.75, Institute of Physiology of the Czech Academy of Sciences (IPHYS CAS), Vídeňská 1083, 14220, Prague, Czech Republic.
| | - Jitka Špačková
- Laboratory of Mitochondrial Physiology, No.75, Institute of Physiology of the Czech Academy of Sciences (IPHYS CAS), Vídeňská 1083, 14220, Prague, Czech Republic
| | - Klára Gotvaldová
- Laboratory of Mitochondrial Physiology, No.75, Institute of Physiology of the Czech Academy of Sciences (IPHYS CAS), Vídeňská 1083, 14220, Prague, Czech Republic
| | - Aleš Dvořák
- Laboratory of Mitochondrial Physiology, No.75, Institute of Physiology of the Czech Academy of Sciences (IPHYS CAS), Vídeňská 1083, 14220, Prague, Czech Republic
- Institute of Medical Biochemistry and Laboratory Diagnostics, 1st Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Alena Křenková
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences (IOCB CAS), Prague, Czech Republic
| | - Martin Hubálek
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences (IOCB CAS), Prague, Czech Republic
| | - Blanka Holendová
- Laboratory of Mitochondrial Physiology, No.75, Institute of Physiology of the Czech Academy of Sciences (IPHYS CAS), Vídeňská 1083, 14220, Prague, Czech Republic
| | - Libor Vítek
- Institute of Medical Biochemistry and Laboratory Diagnostics, 1st Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Petr Ježek
- Laboratory of Mitochondrial Physiology, No.75, Institute of Physiology of the Czech Academy of Sciences (IPHYS CAS), Vídeňská 1083, 14220, Prague, Czech Republic
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Salimi A, Bahiraei T, Ahdeno S, Vatanpour S, Pourahmad J. Evaluation of Cytotoxic Activity of Betanin Against U87MG Human Glioma Cells and Normal Human Lymphocytes and Its Anticancer Potential Through Mitochondrial Pathway. Nutr Cancer 2020; 73:450-459. [PMID: 32420763 DOI: 10.1080/01635581.2020.1764068] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Recent studies revealed an antioxidant activity and anticancer efficiency of betanin. In this study, we investigated the cytotoxic effects and the possible mechanisms of betanin-induced apoptosis against U87MG human glioma cells and compared the results to those of human normal lymphocytes. MTT assay, caspase-3 activation assays in cells and succinate dehydrogenases (SDH), mitochondrial swelling, reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP), and cytochrome C release assays in isolated mitochondria were obtained from U87MG human glioma cells and noncancerous human lymphocytes The results illustrated the significant cytotoxic effect of betanin on U87MG human glioma cells, with a concentration value that inhibits 50% of the cell growth of 7 µg/ml after 12 h of treatment. MTT assay demonstrated that the betanin is selectively toxic to U87MG human glioma cells, and betanin induced cell apoptosis via activation of caspase-3 along with modulation of apoptosis-related mitochondria. Meanwhile, betanin selectively increased ROS formation, mitochondria swelling, MMP decrease, and cytochrome c release in cancerous mitochondria but in normal mitochondria. Based on the evidence obtained from this study, it is concluded that the betanin is a promising natural compound to fight U87MG human glioma cells via induction of apoptosis through activation of intrinsic pathways.
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Affiliation(s)
- Ahmad Salimi
- Department of Pharmacology and Toxicology, School of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Tannaz Bahiraei
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sana Ahdeno
- Department of Pharmacology and Toxicology, School of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Saba Vatanpour
- Department of Biology, University of British Columbia, Vancouver, Canada
| | - Jalal Pourahmad
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Isocitrate dehydrogenase 2 contributes to radiation resistance of oesophageal squamous cell carcinoma via regulating mitochondrial function and ROS/pAKT signalling. Br J Cancer 2020; 123:126-136. [PMID: 32367071 PMCID: PMC7340793 DOI: 10.1038/s41416-020-0852-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 03/06/2020] [Accepted: 04/01/2020] [Indexed: 11/29/2022] Open
Abstract
Background Antioxidase alleviates the accumulation of radiation-induced reactive oxygen species (ROS) and therefore has strong connections with radioresistance. Isocitrate dehydrogenase 2 (IDH2) facilitates the turnover of antioxidase, but its role in radiotherapeutic efficiency in oesophageal squamous cell carcinoma (ESCC) still remains elusive. Methods The involvement of IDH2 in radiotherapeutic efficacy in ESCC was investigated in vitro and vivo by IDH2 knockdown. IDH2 expression in biopsy specimens of 141 patients was identified to evaluate its clinical significance. Results We found that Kyse510 and Kyse140 cells were more radioresistant and had higher IDH2 expression. In these two cell lines, IDH2 knockdown intensified the radiation-induced ROS overload and oxidative damage on lipid, protein, and nucleic acids. In addition, IDH2 silencing aggravated the radiation-induced mitochondrial dysfunction and cell apoptosis and ultimately promoted radiosensitisation via inhibiting AKT phosphorylation in a ROS-dependent manner. Furthermore, IDH2 depletion facilitated the radiation-induced growth inhibition and cell apoptosis in murine xenografts. Finally, IDH2 expression was correlated with definite chemoradiotherapy (dCRT) efficacy and served as an independent prognostic factor for survival of ESCC patients. Conclusions IDH2 plays a key role in the radioresistance of ESCC. Targeting IDH2 could be a promising regimen to improve radiotherapeutic efficiency in ESCC patients.
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Dai W, Xu L, Yu X, Zhang G, Guo H, Liu H, Song G, Weng S, Dong L, Zhu J, Liu T, Guo C, Shen X. OGDHL silencing promotes hepatocellular carcinoma by reprogramming glutamine metabolism. J Hepatol 2020; 72:909-923. [PMID: 31899205 DOI: 10.1016/j.jhep.2019.12.015] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2019] [Revised: 11/20/2019] [Accepted: 12/04/2019] [Indexed: 01/07/2023]
Abstract
BACKGROUND & AIMS Mitochondrial dysfunction and subsequent metabolic deregulation are commonly observed in cancers, including hepatocellular carcinoma (HCC). When mitochondrial function is impaired, reductive glutamine metabolism is a major cellular carbon source for de novo lipogenesis to support cancer cell growth. The underlying regulators of reductively metabolized glutamine in mitochondrial dysfunction are not completely understood in tumorigenesis. METHODS We systematically investigated the role of oxoglutarate dehydrogenase-like (OGDHL), one of the rate-limiting components of the key mitochondrial multi-enzyme OGDH complex (OGDHC), in the regulation of lipid metabolism in hepatoma cells and mouse xenograft models. RESULTS Lower expression of OGDHL was associated with advanced tumor stage, significantly worse survival and more frequent tumor recurrence in 3 independent cohorts totaling 681 postoperative HCC patients. Promoter hypermethylation and DNA copy deletion of OGDHL were independently correlated with reduced OGDHL expression in HCC specimens. Additionally, OGDHL overexpression significantly inhibited the growth of hepatoma cells in mouse xenografts, while knockdown of OGDHL promoted proliferation of hepatoma cells. Mechanistically, OGDHL downregulation upregulated the α-ketoglutarate (αKG):citrate ratio by reducing OGDHC activity, which subsequently drove reductive carboxylation of glutamine-derived αKG via retrograde tricarboxylic acid cycling in hepatoma cells. Notably, silencing of OGDHL activated the mTORC1 signaling pathway in an αKG-dependent manner, inducing transcription of enzymes with key roles in de novo lipogenesis. Meanwhile, metabolic reprogramming in OGDHL-negative hepatoma cells provided an abundant supply of NADPH and glutathione to support the cellular antioxidant system. The reduction of reductive glutamine metabolism through OGDHL overexpression or glutaminase inhibitors sensitized tumor cells to sorafenib, a molecular-targeted therapy for HCC. CONCLUSION Our findings established that silencing of OGDHL contributed to HCC development and survival by regulating glutamine metabolic pathways. OGDHL is a promising prognostic biomarker and therapeutic target for HCC. LAY SUMMARY Hepatocellular carcinoma (HCC) is one of the most prevalent tumors worldwide and is correlated with a high mortality rate. In patients with HCC, lower expression of the enzyme OGDHL is significantly associated with worse survival. Herein, we show that silencing of OGDHL induces lipogenesis and influences the chemosensitization effect of sorafenib in liver cancer cells by reprogramming glutamine metabolism. OGDHL is a promising prognostic biomarker and potential therapeutic target in OGDHL-negative liver cancer.
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Affiliation(s)
- Weiqi Dai
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
| | - Ling Xu
- Department of Gastroenterology, Shanghai Tongren Hospital, Jiaotong University of Medicine, Shanghai, P.R. China
| | - Xiangnan Yu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
| | - Guangcong Zhang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
| | - Hongying Guo
- Department of Severe Hepatitis, Shanghai Public Health Clinical Center, Fudan University, Shanghai, P.R. China
| | - Hailin Liu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
| | - Guangqi Song
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
| | - Shuqiang Weng
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
| | - Ling Dong
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
| | - Jimin Zhu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
| | - Taotao Liu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
| | - Chuanyong Guo
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, P.R. China.
| | - Xizhong Shen
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, P.R. China; Shanghai Institute of Liver Diseases, Shanghai, P.R. China; Key Laboratory of Medical Molecular Virology, Ministry of Education and Health, Shanghai, P.R. China.
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Noh MR, Kong MJ, Han SJ, Kim JI, Park KM. Isocitrate dehydrogenase 2 deficiency aggravates prolonged high-fat diet intake-induced hypertension. Redox Biol 2020; 34:101548. [PMID: 32388270 PMCID: PMC7210593 DOI: 10.1016/j.redox.2020.101548] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 04/16/2020] [Accepted: 04/20/2020] [Indexed: 02/07/2023] Open
Abstract
The development of hypertension is associated with mitochondrial redox balance disruptions. NADP+-dependent isocitrate dehydrogenase 2 (IDH2) plays an important role in the maintenance of mitochondrial redox balance by producing mitochondrial NADPH, which is an essential cofactor in the reduction of glutathione (from GSSG to GSH) to reduced form of glutathione (GSH). We investigated the association of IDH2 between the development of prolonged high-fat diet (HFD)-induced hypertension. Idh2 gene-deleted (Idh2-/-) male mice and wild-type (Idh2+/+) littermates were fed either HFD or low-fat diet (LFD). Some mice were administrated with Mito-TEMPO, a mitochondria-specific antioxidant. HFD feeding increased blood pressure (BP) in both Idh2-/- mice and Idh2+/+ mice. HFD-induced BP increase was greater in Idh2-/- than Idh2+/+ mice. HFD intake decreased IDH2 activity, NADPH levels, and the GSH/(GSH + GSSG) ratio in the renal mitochondria. However, HFD intake increased mitochondrial ROS levels, along with the accompanying oxidative stress and damage. HFD intake increased angiotensin II receptor 1 type 1 mRNA levels in the kidneys and plasma renin and angiotensin II concentrations. These HFD-induced changes were more prominent in Idh2-/- mice than Idh2+/+ mice. Mito-TEMPO mitigated the HFD-induced changes in both Idh2-/- and Idh2+/+ mice, with greater effects in Idh2-/- mice than Idh2+/+ mice. These results indicate that prolonged HFD intake disrupts the IDH2-NADPH-GSH-associated antioxidant system and activates the renin-angiotensin system in the kidney, leading to increased BP, suggesting that IDH2 is a critical enzyme in the development of hypertension and that the IDH2-associated antioxidant system could serve as a potential hypertension treatment target.
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Affiliation(s)
- Mi Ra Noh
- Department of Anatomy, Cardiovascular Research Center and BK21 Plus, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Junggu, Daegu, 41944, Republic of Korea
| | - Min Jung Kong
- Department of Anatomy, Cardiovascular Research Center and BK21 Plus, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Junggu, Daegu, 41944, Republic of Korea
| | - Sang Jun Han
- Department of Anatomy, Cardiovascular Research Center and BK21 Plus, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Junggu, Daegu, 41944, Republic of Korea
| | - Jee In Kim
- Department of Molecular Medicine, Keimyung University School of Medicine, 1095 Dalgubeol-daero, Dalseogu, Daegu, 42601, Republic of Korea
| | - Kwon Moo Park
- Department of Anatomy, Cardiovascular Research Center and BK21 Plus, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Junggu, Daegu, 41944, Republic of Korea.
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Transcriptomic Analysis of Glioma Based on IDH Status Identifies ACAA2 as a Prognostic Factor in Lower Grade Glioma. BIOMED RESEARCH INTERNATIONAL 2020; 2020:1086792. [PMID: 32280672 PMCID: PMC7115055 DOI: 10.1155/2020/1086792] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 02/05/2020] [Indexed: 01/01/2023]
Abstract
Background Glioma is the most common and lethal tumor in the central nervous system (CNS). More than 70% of WHO grade II/III gliomas were found to harbor isocitrate dehydrogenase (IDH) mutations which generated targetable metabolic vulnerabilities. Focusing on the metabolic vulnerabilities, some targeted therapies, such as NAMPT, have shown significant effects in preclinical and clinical trials. Methods We explored the TCGA as well as CGGA database and analyzed the RNA-seq data of lower grade gliomas (LGG) with the method of weighted correlation network analysis (WGCNA). Differential expressed genes were screened, and coexpression relationships were grouped together by performing average linkage hierarchical clustering on the topological overlap. Clinical data were used to conduct Kaplan–Meier analysis. Results In this study, we identified ACAA2 as a prognostic factor in IDH mutation lower grade glioma with the method of weighted correlation network analysis (WGCNA). The difference of ACAA2 gene expressions between the IDH wild-type (IDH-WT) group and the IDH mutant (IDH-MUT) group suggested that there may be different potential targeted therapies based on the fatty acid metabolic vulnerabilities, which promoted the personalized treatment for LGG patients.
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Lee JH, Go Y, Kim DY, Lee SH, Kim OH, Jeon YH, Kwon TK, Bae JH, Song DK, Rhyu IJ, Lee IK, Shong M, Oh BC, Petucci C, Park JW, Osborne TF, Im SS. Isocitrate dehydrogenase 2 protects mice from high-fat diet-induced metabolic stress by limiting oxidative damage to the mitochondria from brown adipose tissue. Exp Mol Med 2020; 52:238-252. [PMID: 32015410 PMCID: PMC7062825 DOI: 10.1038/s12276-020-0379-z] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 12/19/2019] [Accepted: 12/27/2019] [Indexed: 12/14/2022] Open
Abstract
Isocitrate dehydrogenase 2 (IDH2) is an NADP+-dependent enzyme that catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate in the mitochondrial matrix, and is critical for the production of NADPH to limit the accumulation of mitochondrial reactive oxygen species (ROS). Here, we showed that high-fat diet (HFD) feeding resulted in accelerated weight gain in the IDH2KO mice due to a reduction in whole-body energy expenditure. Moreover, the levels of NADP+, NADPH, NAD+, and NADH were significantly decreased in the brown adipose tissue (BAT) of the HFD-fed IDH2KO animals, accompanied by decreased mitochondrial function and reduced expression of key genes involved in mitochondrial biogenesis, energy expenditure, and ROS resolution. Interestingly, these changes were partially reversed when the antioxidant butylated hydroxyanisole was added to the HFD. These observations reveal a crucial role for IDH2 in limiting ROS-dependent mitochondrial damage when BAT metabolism is normally enhanced to limit weight gain in response to dietary caloric overload.
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Affiliation(s)
- Jae-Ho Lee
- Department of Physiology, Keimyung University School of Medicine, Daegu, 42601 Republic of Korea
| | - Younghoon Go
- Department of Internal Medicine, School of Medicine Kyungpook National University, Kyungpook National University Hospital, Daegu, 41944 Republic of Korea
- Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, 41404 South Korea
- Korean Medicine Application Center, Korea Institute of Oriental Medicine, Daegu, 41062 Republic of Korea
| | - Do-Young Kim
- Department of Physiology, Keimyung University School of Medicine, Daegu, 42601 Republic of Korea
| | - Sun Hee Lee
- Department of Physiology, Keimyung University School of Medicine, Daegu, 42601 Republic of Korea
| | - Ok-Hee Kim
- Department of Physiology, Lee Gil Ya Cancer and Diabetes Institute, Gachon University School of Medicine, Younsoo-gu, Inchon, 21999 Republic of Korea
| | - Yong Hyun Jeon
- Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061 Republic of Korea
| | - Taeg Kyu Kwon
- Department of Immunology, Keimyung University School of Medicine, Daegu, 42601 Republic of Korea
| | - Jae-Hoon Bae
- Department of Physiology, Keimyung University School of Medicine, Daegu, 42601 Republic of Korea
| | - Dae-Kyu Song
- Department of Physiology, Keimyung University School of Medicine, Daegu, 42601 Republic of Korea
| | - Im Joo Rhyu
- Department of Anatomy, Korea University College of Medicine, Seoul, 02841 Republic of Korea
| | - In-Kyu Lee
- Department of Internal Medicine, School of Medicine Kyungpook National University, Kyungpook National University Hospital, Daegu, 41944 Republic of Korea
- Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, 41404 South Korea
| | - Minho Shong
- Research Center for Endocrinology and Metabolism, Chungnam National University Hospital (CNUH), 282 Munhwaro, Daejeon, 35015 Republic of Korea
| | - Byung-Chul Oh
- Department of Physiology, Lee Gil Ya Cancer and Diabetes Institute, Gachon University School of Medicine, Younsoo-gu, Inchon, 21999 Republic of Korea
| | - Christopher Petucci
- Center for Metabolic Origins of Disease, Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL 32827 USA
- Cardiovascular Institute and Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104 USA
| | - Jeen-Woo Park
- School of Life Sciences and Biotechnology, College of Natural Science, Kyungpook National University, Daegu, 41566 Republic of Korea
| | - Timothy F. Osborne
- Institute for Fundamental Biomedical Research, Department of Medicine and Biological Chemistry, Johns Hopkins University School of Medicine, St. Petersburg, FL 33701 USA
| | - Seung-Soon Im
- Department of Physiology, Keimyung University School of Medicine, Daegu, 42601 Republic of Korea
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45
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Gelman SJ, Naser F, Mahieu NG, McKenzie LD, Dunn GP, Chheda MG, Patti GJ. Consumption of NADPH for 2-HG Synthesis Increases Pentose Phosphate Pathway Flux and Sensitizes Cells to Oxidative Stress. Cell Rep 2019; 22:512-522. [PMID: 29320744 PMCID: PMC6053654 DOI: 10.1016/j.celrep.2017.12.050] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Revised: 11/03/2017] [Accepted: 12/14/2017] [Indexed: 01/21/2023] Open
Abstract
Gain-of-function mutations in isocitrate dehydroge-nase 1 (IDH1) occur in multiple types of human cancer. Here, we show that these mutations significantly disrupt NADPH homeostasis by consuming NADPH for 2-hydroxyglutarate (2-HG) synthesis. Cells respond to 2-HG synthesis, but not exogenous administration of 2-HG, by increasing pentose phosphate pathway (PPP) flux. We show that 2-HG production competes with reductive biosynthesis and the buffering of oxidative stress, processes that also require NADPH. IDH1 mutants have a decreased capacity to synthesize palmitate and an increased sensitivity to oxidative stress. Our results demonstrate that, even when NADPH is limiting, IDH1 mutants continue to synthesize 2-HG at the expense of other NADPH-requiring pathways that are essential for cell viability. Thus, rather than attempting to decrease 2-HG synthesis in the clinic, the consumption of NADPH by mutant IDH1 may be exploited as a metabolic weakness that sensitizes tumor cells to ionizing radiation, a commonly used anti-cancer therapy.
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Affiliation(s)
- Susan J Gelman
- Department of Chemistry, Washington University, St. Louis, MO 63130, USA
| | - Fuad Naser
- Department of Chemistry, Washington University, St. Louis, MO 63130, USA
| | - Nathaniel G Mahieu
- Department of Chemistry, Washington University, St. Louis, MO 63130, USA
| | - Lisa D McKenzie
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Gavin P Dunn
- Departments of Neurological Surgery and Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Milan G Chheda
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Gary J Patti
- Department of Chemistry, Washington University, St. Louis, MO 63130, USA; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
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Radiosensitization and a Less Aggressive Phenotype of Human Malignant Glioma Cells Expressing Isocitrate Dehydrogenase 1 (IDH1) Mutant Protein: Dissecting the Mechanisms. Cancers (Basel) 2019; 11:cancers11060889. [PMID: 31242696 PMCID: PMC6627228 DOI: 10.3390/cancers11060889] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 06/09/2019] [Accepted: 06/11/2019] [Indexed: 01/02/2023] Open
Abstract
The presence of an isocitrate dehydrogenase 1 (IDH1) mutation is associated with a less aggressive phenotype, increased sensitivity to radiation, and increased overall survival in patients with diffuse glioma. Based on in vitro experimentations in malignant glioma cell lines, the consequences on cellular processes of IDH1R132H expression were analyzed. The results revealed that IDH1R132H expression enhanced the radiation induced accumulation of residual γH2AX foci and decreased the amount of glutathione (GSH) independent of the oxygen status. In addition, expression of the mutant IDH1 caused a significant increase of cell stiffness and induced an altered organization of the cytoskeleton, which has been shown to reinforce cell stiffness. Furthermore, IDH1R132H expression decreased the expression of vimentin, an important component of the cytoskeleton and regulator of the cell stiffness. The results emphasize the important role of mutant IDH1 in treatment of patients with diffuse gliomas especially in response to radiation. Hence, detection of the genetic status of IDH1 before therapy massively expands the utility of immunohistochemistry to accurately distinguish patients with a less aggressive and radiosensitive IDH1-mutant diffuse glioma suitable for radiotherapy from those with a more aggressive IDH1-wildtype diffuse glioma who might benefit from an individually intensified therapy comprising radiotherapy and alternative medical treatments.
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Zhang Y, Lv W, Li Q, Wang Q, Ru Y, Xiong X, Yan F, Pan T, Lin W, Li X. IDH2 compensates for IDH1 mutation to maintain cell survival under hypoxic conditions in IDH1‑mutant tumor cells. Mol Med Rep 2019; 20:1893-1900. [PMID: 31257503 DOI: 10.3892/mmr.2019.10418] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Accepted: 05/01/2019] [Indexed: 11/06/2022] Open
Abstract
Mutations of isocitrate dehydrogenase (IDH) 1 and 2 occur in low‑grade gliomas, acute myeloid leukemias and other types of solid cancer. By catalyzing the reversible conversion between isocitrate and α‑ketoglutarate (α‑KG), IDH1 and 2 contribute to the central process of metabolism, including oxidative and reductive metabolism. IDH1 and 2 mutations result in the loss of normal catalytic function and acquire neomorphic activity, facilitating the conversion of α‑KG into an oncometabolite, (R)‑2‑hydroxyglutarate, which can cause epigenetic modifications and tumorigenesis. Small‑molecule inhibitors of mutant IDH1 and 2 have been developed, and ongoing clinical trials have shown promising results in hematological malignancies, but not in gliomas. These previous findings make it necessary to identify the mechanism and develop more effective therapies for IDH1‑mutant gliomas. In the present study, it was demonstrated that under hypoxic conditions, patient‑derived primary glioma cells and HCT116 cells, both of which carry a monoallelic IDH1 arginine 132 to histidine mutation (R132H), have a slower growth rate than the corresponding wild‑type IDH1 cells. Western blot analysis showed that IDH1 R132H‑mutant cancer cells exhibited upregulated IDH2 protein expression under hypoxic conditions. Furthermore, the silencing of IDH2 using small interfering RNA significantly inhibited the growth of IDH1‑mutant cells under hypoxic conditions. Finally, [U‑13C5]glutamine tracer analysis showed that IDH2 knockdown reduced the reductive carboxylation of α‑KG into isocitrate in HCT116R132H/+ cells under hypoxic conditions. The present study showed for the first time, to the best of our knowledge, that IDH2 plays a compensatory role in maintaining reductive carboxylation‑dependent lipogenesis and proliferation in IDH1 R132H tumor cells. Therefore, IDH2 could serve as a potential anti‑tumor target for IDH1‑mutant tumors, which may provide a new strategy for treatment.
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Affiliation(s)
- Yao Zhang
- Department of Neurosurgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Weifeng Lv
- Department of Neurosurgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Qi Li
- Department of Neurosurgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Qinhao Wang
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Yi Ru
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Xin Xiong
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Fengqi Yan
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Tao Pan
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Wei Lin
- Department of Neurosurgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Xia Li
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
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48
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Peeters TH, Lenting K, Breukels V, van Lith SAM, van den Heuvel CNAM, Molenaar R, van Rooij A, Wevers R, Span PN, Heerschap A, Leenders WPJ. Isocitrate dehydrogenase 1-mutated cancers are sensitive to the green tea polyphenol epigallocatechin-3-gallate. Cancer Metab 2019; 7:4. [PMID: 31139406 PMCID: PMC6526618 DOI: 10.1186/s40170-019-0198-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Accepted: 04/09/2019] [Indexed: 01/09/2023] Open
Abstract
Background Mutations in isocitrate dehydrogenase 1 (IDH1) occur in various types of cancer and induce metabolic alterations resulting from the neomorphic activity that causes production of D-2-hydroxyglutarate (D-2-HG) at the expense of α-ketoglutarate (α-KG) and NADPH. To overcome metabolic stress induced by these alterations, IDH-mutated (IDHmut) cancers utilize rescue mechanisms comprising pathways in which glutaminase and glutamate dehydrogenase (GLUD) are involved. We hypothesized that inhibition of glutamate processing with the pleiotropic GLUD-inhibitor epigallocatechin-3-gallate (EGCG) would not only hamper D-2-HG production, but also decrease NAD(P)H and α-KG synthesis in IDHmut cancers, resulting in increased metabolic stress and increased sensitivity to radiotherapy. Methods We performed 13C-tracing studies to show that HCT116 colorectal cancer cells with an IDH1R132H knock-in allele depend more on glutaminolysis than on glycolysis for the production of D-2-HG. We treated HCT116 cells, HCT116-IDH1R132H cells, and HT1080 cells (carrying an IDH1R132C mutation) with EGCG and evaluated D-2-HG production, cell proliferation rates, and sensitivity to radiotherapy. Results Significant amounts of 13C from glutamate accumulate in D-2-HG in HCT116-IDH1wt/R132H but not in HCT116-IDH1wt/wt. Preventing glutamate processing in HCT116-IDH1wt/R132H cells with EGCG resulted in reduction of D-2-HG production. In addition, EGCG treatment decreased proliferation rates of IDH1mut cells and at high doses sensitized cancer cells to ionizing radiation. Effects of EGCG in IDH-mutated cell lines were diminished by treatment with the IDH1mut inhibitor AGI-5198. Conclusions This work shows that glutamate can be directly processed into D-2-HG and that reduction of glutamatolysis may be an effective and promising new treatment option for IDHmut cancers. Electronic supplementary material The online version of this article (10.1186/s40170-019-0198-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Tom H Peeters
- 1Department of Radiology and Nuclear Medicine, Radboud university medical center, PO Box 9101, 6500 Nijmegen, HB The Netherlands
| | - Krissie Lenting
- 2Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Geert Grooteplein 26, 6525 Nijmegen, GA The Netherlands
| | - Vincent Breukels
- 1Department of Radiology and Nuclear Medicine, Radboud university medical center, PO Box 9101, 6500 Nijmegen, HB The Netherlands
| | - Sanne A M van Lith
- 1Department of Radiology and Nuclear Medicine, Radboud university medical center, PO Box 9101, 6500 Nijmegen, HB The Netherlands
| | - Corina N A M van den Heuvel
- 2Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Geert Grooteplein 26, 6525 Nijmegen, GA The Netherlands
| | - Remco Molenaar
- 3Department of Medical Biology, Cancer Center Amsterdam at the Academic Medical Center, Meibergdreef 15, 1105 Amsterdam, AZ The Netherlands
| | - Arno van Rooij
- 4Department of Laboratory Medicine, Radboud university medical center, PO Box 9101, 6500 Nijmegen, HB The Netherlands
| | - Ron Wevers
- 4Department of Laboratory Medicine, Radboud university medical center, PO Box 9101, 6500 Nijmegen, HB The Netherlands
| | - Paul N Span
- 5Department of Radiation Oncology, Radiotherapy and OncoImmunology Laboratory, Radboud university medical center, PO Box 9101, 6500 Nijmegen, HB The Netherlands
| | - Arend Heerschap
- 1Department of Radiology and Nuclear Medicine, Radboud university medical center, PO Box 9101, 6500 Nijmegen, HB The Netherlands
| | - William P J Leenders
- 2Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Geert Grooteplein 26, 6525 Nijmegen, GA The Netherlands
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49
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Dai X, Luo Y, Xu Y, Zhang J. Key indexes and the emerging tool for tumor microenvironment editing. Am J Cancer Res 2019; 9:1027-1042. [PMID: 31218110 PMCID: PMC6556601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 03/25/2019] [Indexed: 06/09/2023] Open
Abstract
Many cancer management approaches including immunotherapies can not achieve desirable therapeutic efficacies if targeting tumors alone or could not effectively reach tumor cells. The concept of tumor microenvironment and its induced gene reprogramming have largely extended our current understandings on the determinants of tumor initiation/progression and fostered our hope in establishing first-line therapies targeting cancer microenvironment or adjuvant therapies enhancing the efficacies of existing oncotherapeutic modalities such as immunotherapies for efficient cancer management. This review identifies key indexes of tumor microenvironment, i.e., hypoxia, acidosis, hypo-nutrition and inflammation, which collectively determine the feature and the fate of adjacent tumor cells, and proposes cold atmospheric plasma, the fourth state of matter that is largely composed of various reactive oxygen and nitrogen species, as a promising tool for tumor microenvironment editing. We propose that cold atmospheric plasma represents an emerging onco-therapeutic strategy alone or complementing existing treatment approaches given its multi-modal nature through tumor microenvironment modulation.
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Affiliation(s)
- Xiaofeng Dai
- Wuxi School of Medicine, Jiangnan UniversityWuxi, China
| | - Yini Luo
- School of Biotechnology, Jiangnan UniversityWuxi, China
| | - Ying Xu
- School of Biotechnology, Jiangnan UniversityWuxi, China
| | - Jianying Zhang
- Department of Biological Sciences, University of Texas at El PasoTexas 79968, USA
- Academy of Medical and Pharmaceutical Sciences, Zhengzhou UniversityZhengzhou, China
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50
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Kotredes KP, Razmpour R, Lutton E, Alfonso-Prieto M, Ramirez SH, Gamero AM. Characterization of cancer-associated IDH2 mutations that differ in tumorigenicity, chemosensitivity and 2-hydroxyglutarate production. Oncotarget 2019; 10:2675-2692. [PMID: 31105869 PMCID: PMC6505628 DOI: 10.18632/oncotarget.26848] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2018] [Accepted: 03/23/2019] [Indexed: 01/01/2023] Open
Abstract
The family of isocitrate dehydrogenase (IDH) enzymes is vital for cellular metabolism, as IDH1 and IDH2 are required for the decarboxylation of isocitrate to α-ketoglutarate. Heterozygous somatic mutations in IDH1 or IDH2 genes have been detected in many cancers. They share the neomorphic production of the oncometabolite (R)-2-hydroxyglutarate [(R)-2-HG]. With respect to IDH2, it is unclear whether all IDH2 mutations display the same or differ in tumorigenic properties and degrees of chemosensitivity. Here, we evaluated the three most frequent IDH2 mutations occurring in cancer. The predicted changes to the enzyme structure introduced by these individual mutations are supported by the observed production of (R)-2-HG. However, their tumorigenic properties, response to chemotherapeutic agents, and baseline activation of STAT3 differed. Paradoxically, the varying levels of endogenous (R)-2-HG produced by each IDH2 mutant inversely correlated with their respective growth rates. Interestingly, while we found that (R)-2-HG stimulated the growth of non-transformed cells, (R)-2-HG also displayed antitumor activity by suppressing the growth of tumors harboring wild type IDH2. The mitogenic effect of (R)-2-HG in immortalized cells could be switched to antiproliferative by transformation with oncogenic RAS. Thus, our findings show that despite their shared (R)-2-HG production, IDH2 mutations are not alike and differ in shaping tumor cell behavior and response to chemotherapeutic agents. Our study also reveals that under certain conditions, (R)-2-HG has antitumor properties.
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Affiliation(s)
- Kevin P Kotredes
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
| | - Roshanak Razmpour
- Department of Pathology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
| | - Evan Lutton
- Department of Pathology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
| | - Mercedes Alfonso-Prieto
- Department of Inorganic and Organic Chemistry, University of Barcelona, Barcelona, Spain.,Computational Biomedicine, Institute for Advanced Simulation IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich, Jülich, Germany.,C. and O. Vogt Institute for Brain Research, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
| | - Servio H Ramirez
- Department of Pathology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
| | - Ana M Gamero
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
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