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Tytuł:
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Targeting IDH1 as a Prosenescent Therapy in High-grade Serous Ovarian Cancer.
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Autorzy:
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Dahl ES; Department of Cellular & Molecular Physiology, Penn State College of Medicine, Hershey, Pennsylvania.
Buj R; Department of Cellular & Molecular Physiology, Penn State College of Medicine, Hershey, Pennsylvania.
Leon KE; Department of Cellular & Molecular Physiology, Penn State College of Medicine, Hershey, Pennsylvania.
Newell JM; Department of Pathology, Penn State College of Medicine, Hershey, Pennsylvania.
Imamura Y; Department of Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania.
Bitler BG; Division of Reproductive Sciences, University of Colorado Anschutz Medical Campus, Denver, Colorado.
Snyder NW; AJ Drexel Autism Institute, Drexel University, Philadelphia, Pennsylvania.
Aird KM; Department of Cellular & Molecular Physiology, Penn State College of Medicine, Hershey, Pennsylvania. .
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Źródło:
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Molecular cancer research : MCR [Mol Cancer Res] 2019 Aug; Vol. 17 (8), pp. 1710-1720. Date of Electronic Publication: 2019 May 20.
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Typ publikacji:
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Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Original Publication: Philadelphia, PA : American Association for Cancer Research, c2002-
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MeSH Terms:
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Cellular Senescence*
Gene Expression Regulation, Neoplastic*
Carcinoma, Ovarian Epithelial/*pathology
Cystadenocarcinoma, Serous/*pathology
E2F Transcription Factors/*metabolism
Histones/*metabolism
Isocitrate Dehydrogenase/*metabolism
Apoptosis ; Carcinoma, Ovarian Epithelial/genetics ; Carcinoma, Ovarian Epithelial/metabolism ; Cell Proliferation ; Cystadenocarcinoma, Serous/genetics ; Cystadenocarcinoma, Serous/metabolism ; E2F Transcription Factors/genetics ; Epigenesis, Genetic ; Female ; Histones/genetics ; Humans ; Isocitrate Dehydrogenase/genetics ; Neoplasm Grading ; Survival Rate ; Tumor Cells, Cultured
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References:
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Grant Information:
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F31 CA236372 United States CA NCI NIH HHS; R00 CA194318 United States CA NCI NIH HHS; R00 CA194309 United States CA NCI NIH HHS; P30 ES013508 United States ES NIEHS NIH HHS; R03 CA211820 United States CA NCI NIH HHS
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Substance Nomenclature:
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0 (E2F Transcription Factors)
0 (Histones)
EC 1.1.1.41 (Isocitrate Dehydrogenase)
EC 1.1.1.42. (IDH1 protein, human)
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Entry Date(s):
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Date Created: 20190522 Date Completed: 20200416 Latest Revision: 20200801
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Update Code:
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20240104
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PubMed Central ID:
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PMC6679739
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DOI:
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10.1158/1541-7786.MCR-18-1233
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PMID:
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31110157
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Epithelial ovarian cancer (EOC) is the deadliest gynecologic cancer. High-grade serous carcinoma (HGSC) is the most frequently diagnosed and lethal histosubtype of EOC. A significant proportion of patients with HGSC relapse with chemoresistant disease. Therefore, there is an urgent need for novel therapeutic strategies for HGSC. Metabolic reprogramming is a hallmark of cancer cells, and targeting metabolism for cancer therapy may be beneficial. Here, we found that in comparison with normal fallopian tube epithelial cells, HGSC cells preferentially utilize glucose in the TCA cycle and not for aerobic glycolysis. This correlated with universally increased TCA cycle enzyme expression in HGSC cells under adherent conditions. HGSC disseminates as tumor cell spheroids within the peritoneal cavity. We found that wild-type isocitrate dehydrogenase I ( IDH1 ) is the only TCA cycle enzyme upregulated in both adherent and spheroid conditions and is associated with reduced progression-free survival. IDH1 protein expression is also increased in patients with primary HGSC tumors. Pharmacologic inhibition or knockdown of IDH1 decreased proliferation of multiple HGSC cell lines by inducing senescence. Mechanistically, suppression of IDH1 increased the repressive histone mark H3K9me2 at multiple E2F target gene loci, which led to decreased expression of these genes. Altogether, these data suggest that increased IDH1 activity is an important metabolic adaptation in HGSC and that targeting wild-type IDH1 in HGSC alters the repressive histone epigenetic landscape to induce senescence. IMPLICATIONS: Inhibition of IDH1 may act as a novel therapeutic approach to alter both the metabolism and epigenetics of HGSC as a prosenescent therapy.
(©2019 American Association for Cancer Research.)
Erratum in: Mol Cancer Res. 2020 May;18(5):797. (PMID: 32366697)
Comment in: Ann Transl Med. 2020 Jun;8(12):780. (PMID: 32647705)