Mutant IDH regulates glycogen metabolism from early cartilage development to malignant chondrosarcoma formation.

Autor:	Pathmanapan S; Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada., Poon R; Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada., De Renshaw TB; Department of Orthopaedic Surgery, Duke University, Durham, NC, USA., Nadesan P; Department of Orthopaedic Surgery, Duke University, Durham, NC, USA., Nakagawa M; Department of Orthopaedic Surgery, Duke University, Durham, NC, USA., Seesankar GA; Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada., Ho Loe AK; Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada., Zhang HH; Department of Orthopaedic Surgery, Duke University, Durham, NC, USA., Guinovart JJ; Institute for Research in Biomedicine (IRB Barcelona) Barcelona, Barcelona, Spain., Duran J; Institute for Research in Biomedicine (IRB Barcelona) Barcelona, Barcelona, Spain., Newgard CB; Department of Pharmacology & Cancer Biology, Duke University, Durham, NC, USA; Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA., Wunder JS; Lunenfeld-Tanenbaum Research Institute and the University Musculoskeletal Oncology Unit, Mount Sinai Hospital, Toronto, ON, Canada., Alman BA; Department of Orthopaedic Surgery, Duke University, Durham, NC, USA. Electronic address: ben.alman@duke.edu.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2023 Jun 27; Vol. 42 (6), pp. 112578. Date of Electronic Publication: 2023 Jun 01.
DOI:	10.1016/j.celrep.2023.112578
Abstrakt:	Chondrosarcomas are the most common malignancy of cartilage and are associated with somatic mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 genes. Somatic IDH mutations are also found in its benign precursor lesion, enchondromas, suggesting that IDH mutations are early events in malignant transformation. Human mutant IDH chondrosarcomas and mutant Idh mice that develop enchondromas investigated in our studies display glycogen deposition exclusively in mutant cells from IDH mutant chondrosarcomas and Idh1 mutant murine growth plates. Pharmacologic blockade of glycogen utilization induces changes in tumor cell behavior, downstream energetic pathways, and tumor burden in vitro and in vivo. Mutant IDH1 interacts with hypoxia-inducible factor 1α (HIF1α) to regulate expression of key enzymes in glycogen metabolism. Here, we show a critical role for glycogen in enchondromas and chondrosarcomas, which is likely mediated through an interaction with mutant IDH1 and HIF1α. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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