2. Academic Validation
  3. Loss of SDHB Promotes Dysregulated Iron Homeostasis, Oxidative Stress, and Sensitivity to Ascorbate

Loss of SDHB Promotes Dysregulated Iron Homeostasis, Oxidative Stress, and Sensitivity to Ascorbate

  • Cancer Res. 2021 Jul 1;81(13):3480-3494. doi: 10.1158/0008-5472.CAN-20-2936.
Judith Goncalves 1 2,  Sophie Moog  # 1 2,  Aurélie Morin  # 1 2,  Géraldine Gentric 3,  Sebastian Müller 4,  Alexander P Morrell 5,  Katarina Kluckova 6,  Theodora J Stewart 7,  Cynthia L Andoniadou 8,  Charlotte Lussey-Lepoutre 1 9,  Paule Bénit 10,  Alpesh Thakker 6,  Lisa Vettore 6,  Jennie Roberts 6,  Raphaël Rodriguez 4,  Fatima Mechta-Grigoriou 3,  Anne-Paule Gimenez-Roqueplo 1 2 11,  Eric Letouzé 12,  Daniel A Tennant 6,  Judith Favier 13 2
Affiliations

Affiliations

  • 1 PARCC, INSERM UMR970, Equipe Labellisée par la Ligue Contre le Cancer, Paris, France.
  • 2 Université de Paris, Paris, France.
  • 3 Stress and Cancer Laboratory, Institut Curie, Equipe Labellisée par la Ligue Nationale contre le Cancer, Inserm U830, PSL Research University, Paris France.
  • 4 Chemical Biology of Cancer Team, Equipe Labellisée par la Ligue Contre le Cancer, PSL Research University, CNRS UMR3666 -INSERM U1143, Institut Curie, Paris, France.
  • 5 Centre for Oral, Clinical & Translational Sciences, Faculty of Dentistry, Oral and Craniofacial Sciences, King's College London, London, United Kingdom.
  • 6 Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham, \United Kingdom.
  • 7 London Metallomics Facility, King's College London and Imperial College London, London, United Kingdom.
  • 8 Centre for Oral, Clinical & Translational Sciences, Faculty of Dentistry, Oral and Craniofacial Sciences, King's College London.
  • 9 Sorbonne Université, Pitie-Salpêtrière Hospital, Department of Nuclear Medicine, Assistance Publique-Hôpitaux de Paris, Paris, France.
  • 10 Université de Paris, INSERM, UMR 1141, Hôpital Robert Debré, Paris, France.
  • 11 Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Department of Genetics, Paris, France.
  • 12 Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, INSERM, Equipe Labellisée par la Ligue Nationale Contre le Cancer, Paris France.
  • 13 PARCC, INSERM UMR970, Equipe Labellisée par la Ligue Contre le Cancer, Paris, France. [email protected].
  • # Contributed equally.
PMID: 34127497 DOI: 10.1158/0008-5472.CAN-20-2936
Abstract

Succinate dehydrogenase is a key Enzyme in the tricarboxylic acid cycle and the electron transport chain. All four subunits of succinate dehydrogenase are tumor suppressor genes predisposing to paraganglioma, but only mutations in the SDHB subunit are associated with increased risk of metastasis. Here we generated an Sdhd knockout chromaffin cell line and compared it with Sdhb-deficient cells. Both cell types exhibited similar SDH loss of function, metabolic adaptation, and succinate accumulation. In contrast, Sdhb-/- cells showed hallmarks of mesenchymal transition associated with increased DNA hypermethylation and a stronger pseudo-hypoxic phenotype compared with Sdhd-/- cells. Loss of SDHB specifically led to increased oxidative stress associated with dysregulated iron and copper homeostasis in the absence of NRF2 activation. High-dose ascorbate exacerbated the increase in mitochondrial Reactive Oxygen Species, leading to cell death in Sdhb-/- cells. These data establish a mechanism linking oxidative stress to iron homeostasis that specifically occurs in Sdhb-deficient cells and may promote metastasis. They also highlight high-dose ascorbate as a promising therapeutic strategy for SDHB-related cancers. SIGNIFICANCE: Loss of different succinate dehydrogenase subunits can lead to different cell and tumor phenotypes, linking stronger 2-OG-dependent dioxygenases inhibition, iron overload, and ROS accumulation following SDHB mutation.

Figures
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