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The GAPDH redox switch safeguards reductive capacity and enables survival of stressed tumour cells.
Talwar, Deepti; Miller, Colin G; Grossmann, Justus; Szyrwiel, Lukasz; Schwecke, Torsten; Demichev, Vadim; Mikecin Drazic, Ana-Matea; Mayakonda, Anand; Lutsik, Pavlo; Veith, Carmen; Milsom, Michael D; Müller-Decker, Karin; Mülleder, Michael; Ralser, Markus; Dick, Tobias P.
Afiliación
  • Talwar D; Division of Redox Regulation, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Miller CG; Division of Redox Regulation, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Grossmann J; Department of Biochemistry, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
  • Szyrwiel L; Department of Biochemistry, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
  • Schwecke T; Department of Biochemistry, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
  • Demichev V; Department of Biochemistry, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
  • Mikecin Drazic AM; Division of Experimental Hematology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Mayakonda A; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany.
  • Lutsik P; Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Veith C; Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Milsom MD; Laboratory of Computational Cancer Biology and Epigenomics, Department of Oncology, Catholic University (KU) Leuven, Leuven, Belgium.
  • Müller-Decker K; Division of Redox Regulation, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Mülleder M; Division of Experimental Hematology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Ralser M; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany.
  • Dick TP; Core Facility Tumor Models, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Nat Metab ; 5(4): 660-676, 2023 04.
Article en En | MEDLINE | ID: mdl-37024754
Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is known to contain an active-site cysteine residue undergoing oxidation in response to hydrogen peroxide, leading to rapid inactivation of the enzyme. Here we show that human and mouse cells expressing a GAPDH mutant lacking this redox switch retain catalytic activity but are unable to stimulate the oxidative pentose phosphate pathway and enhance their reductive capacity. Specifically, we find that anchorage-independent growth of cells and spheroids is limited by an elevation of endogenous peroxide levels and is largely dependent on a functional GAPDH redox switch. Likewise, tumour growth in vivo is limited by peroxide stress and suppressed when the GAPDH redox switch is disabled in tumour cells. The induction of additional intratumoural oxidative stress by chemo- or radiotherapy synergized with the deactivation of the GAPDH redox switch. Mice lacking the GAPDH redox switch exhibit altered fatty acid metabolism in kidney and heart, apparently in compensation for the lack of the redox switch. Together, our findings demonstrate the physiological and pathophysiological relevance of oxidative GAPDH inactivation in mammals.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Cisteína / Gliceraldehído-3-Fosfato Deshidrogenasas Límite: Animals / Humans Idioma: En Revista: Nat Metab Año: 2023 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Alemania
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Cisteína / Gliceraldehído-3-Fosfato Deshidrogenasas Límite: Animals / Humans Idioma: En Revista: Nat Metab Año: 2023 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Alemania