Cellular signals converge at the NOX2-SHP-2 axis to induce reductive carboxylation in cancer cells.

Autor:	Zhang R; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Medicine, The University of Chicago, Chicago, IL 60637, USA., Chen D; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA., Fan H; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Medicine, The University of Chicago, Chicago, IL 60637, USA., Wu R; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Medicine, The University of Chicago, Chicago, IL 60637, USA., Tu J; Department of Medicine, The University of Chicago, Chicago, IL 60637, USA., Zhang FQ; Department of Medicine, The University of Chicago, Chicago, IL 60637, USA., Wang M; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA., Zheng H; Department of Pediatrics and Aflac Cancer and Blood Disorder Center, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA., Qu CK; Department of Pediatrics and Aflac Cancer and Blood Disorder Center, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA., Elf SE; The Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA., Faubert B; Department of Medicine, The University of Chicago, Chicago, IL 60637, USA., He YY; Department of Medicine, The University of Chicago, Chicago, IL 60637, USA., Bissonnette MB; Department of Medicine, The University of Chicago, Chicago, IL 60637, USA., Gao X; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Medicine, The University of Chicago, Chicago, IL 60637, USA. Electronic address: xgao30@uchicago.edu., DeBerardinis RJ; UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: ralph.deberardinis@utsouthwestern.edu., Chen J; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Medicine, The University of Chicago, Chicago, IL 60637, USA. Electronic address: jingchen@medicine.bsd.uchicago.edu.
Jazyk:	angličtina
Zdroj:	Cell chemical biology [Cell Chem Biol] 2022 Jul 21; Vol. 29 (7), pp. 1200-1208.e6. Date of Electronic Publication: 2022 Apr 15.
DOI:	10.1016/j.chembiol.2022.03.010
Abstrakt:	Environmental stresses, including hypoxia or detachment for anchorage independence, or attenuation of mitochondrial respiration through inhibition of electron transport chain induce reductive carboxylation in cells with an enhanced fraction of citrate arising through reductive metabolism of glutamine. This metabolic process contributes to redox homeostasis and sustains biosynthesis of lipids. Reductive carboxylation is often dependent on cytosolic isocitrate dehydrogenase 1 (IDH1). However, whether diverse cellular signals induce reductive carboxylation differentially or through a common signaling converging node remains unclear. We found that induction of reductive carboxylation commonly requires enhanced tyrosine phosphorylation and activation of IDH1, which, surprisingly, is achieved by attenuation of a cytosolic protein tyrosine phosphatase, Src homology region 2 domain-containing phosphatase-2 (SHP-2). Mechanistically, diverse signals induce reductive carboxylation by converging at upregulation of NADPH oxidase 2, leading to elevated cytosolic reactive oxygen species that consequently inhibit SHP-2. Together, our work elucidates the signaling basis underlying reductive carboxylation in cancer cells. Competing Interests: Declaration of interests The authors have no conflicts of interest to declare. (Copyright © 2022 Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
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