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

• Type of Material: Article
• Authors: Rukang Zhang, Emory University; Dong Chen, Emory University; Hao Fan, Emory University; Rong Wu, Emory University; Jiayi Tu, University of Chicago; Freya Q Zhang, University of Chicago; Mei Wang, Emory University; Hong Zheng, Emory University; Cheng-Kui Qu, Emory University; Shannon E Elf, University of Chicago; Brandon Faubert, University of Chicago; Yu-Ying He, University of Chicago; Marc B Bissonnette, University of Chicago; Xue Gao, Emory University; Ralph J DeBerardinis, UT Southwestern Medical Center, Dallas; Jing Chen, Emory University
• Language: English
• Date: 2022-07-21
• Publisher: CELL PRESS
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2022 Elsevier Ltd.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.chembiol.2022.03.010
• Title of Journal or Parent Work: CELL CHEMICAL BIOLOGY
• Volume: 29
• Issue: 7
• Start Page: 1200
• End Page: +
• Keywords: Life Sciences & Biomedicine; APOPTOSIS; GROWTH; METABOLISM; PHYSIOLOGY; Science & Technology; MECHANISMS; SHP-2 TYROSINE PHOSPHATASE; NOX FAMILY; NADPH OXIDASES; Biochemistry & Molecular Biology
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Oncology; Engineering, Biomedical

Abstract

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.