title: Pyruvate carboxylation enables growth of SDH-deficient cells by supporting aspartate biosynthesis.
abstract: Succinate dehydrogenase (SDH) is a heterotetrameric nuclear-encoded complex responsible for the oxidation of succinate to fumarate in the tricarboxylic acid cycle. Loss-of-function mutations in any of the SDH genes are associated with cancer formation. However, the impact of SDH loss on cell metabolism and the mechanisms enabling growth of SDH-defective cells are largely unknown. Here, we generated Sdhb-ablated kidney mouse cells and used comparative metabolomics and stable-isotope-labelling approaches to identify nutritional requirements and metabolic adaptations to SDH loss. We found that lack of SDH activity commits cells to consume extracellular pyruvate, which sustains Warburg-like bioenergetic features. We further demonstrated that pyruvate carboxylation diverts glucose-derived carbons into aspartate biosynthesis, thus sustaining cell growth. By identifying pyruvate carboxylase as essential for the proliferation and tumorigenic capacity of SDH-deficient cells, this study revealed a metabolic vulnerability for potential future treatment of SDH-associated malignancies.
authors: Cancer Research UK, Beatson Institute, Switchback Rd, Glasgow G61 1BD, UK.
authors: Simone
authors: S
authors: Cardaci
authors: Cancer Research UK, Beatson Institute, Switchback Rd, Glasgow G61 1BD, UK.
authors: Liang
authors: L
authors: Zheng
authors: Cancer Research UK, Beatson Institute, Switchback Rd, Glasgow G61 1BD, UK.
authors: Gillian
authors: G
authors: MacKay
authors: Cancer Research UK, Beatson Institute, Switchback Rd, Glasgow G61 1BD, UK.
authors: Niels J F
authors: NJ
authors: van den Broek
authors: Cancer Research UK, Beatson Institute, Switchback Rd, Glasgow G61 1BD, UK.
authors: Elaine D
authors: ED
authors: MacKenzie
authors: Cancer Research UK, Beatson Institute, Switchback Rd, Glasgow G61 1BD, UK.
authors: Colin
authors: C
authors: Nixon
authors: Cancer Research UK, Beatson Institute, Switchback Rd, Glasgow G61 1BD, UK.
authors: David
authors: D
authors: Stevenson
authors: Cancer Research UK, Beatson Institute, Switchback Rd, Glasgow G61 1BD, UK.|Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK.
authors: Sergey
authors: S
authors: Tumanov
authors: Cancer Research UK, Beatson Institute, Switchback Rd, Glasgow G61 1BD, UK.|Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK.
authors: Vinay
authors: V
authors: Bulusu
authors: Cancer Research UK, Beatson Institute, Switchback Rd, Glasgow G61 1BD, UK.|Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK.
authors: Jurre J
authors: JJ
authors: Kamphorst
authors: Cancer Research UK, Beatson Institute, Switchback Rd, Glasgow G61 1BD, UK.
authors: Alexei
authors: A
authors: Vazquez
authors: Department of Pathology, University of Dundee, Ninewells Hospital, Dundee DD1 9SY, UK.
authors: Stewart
authors: S
authors: Fleming
authors: Veneto Institute of Oncology IRCCS, Familial cancer clinic and oncoendocrinology, Via Gattamelata 64, 35128 Padova, Italy.
authors: Francesca
authors: F
authors: Schiavi
authors: Cancer Research UK, Beatson Institute, Switchback Rd, Glasgow G61 1BD, UK.
authors: Gabriela
authors: G
authors: Kalna
authors: Cancer Research UK, Beatson Institute, Switchback Rd, Glasgow G61 1BD, UK.
authors: Karen
authors: K
authors: Blyth
authors: Cancer Research UK, Beatson Institute, Switchback Rd, Glasgow G61 1BD, UK.
authors: Douglas
authors: D
authors: Strathdee
authors: Cancer Research UK, Beatson Institute, Switchback Rd, Glasgow G61 1BD, UK.
authors: Eyal
authors: E
authors: Gottlieb
mesh_terms: D000818:Animals; D001224:Aspartic Acid / Q000096:biosynthesis*; D002264:Carboxylic Acids / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D015151:Immunoblotting; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism; D008297:Male; D055432:Metabolomics / Q000379:methods; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D011766:Pyruvate Carboxylase / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism*; D034622:RNA Interference; D013385:Succinate Dehydrogenase / Q000235:genetics / Q000378:metabolism*
chemical_list: D002264:Carboxylic Acids; D001224:Aspartic Acid; D019289:Pyruvic Acid; D013385:Succinate Dehydrogenase; D011766:Pyruvate Carboxylase