Loss of sdhb promotes dysregulated iron homeostasis, oxidative stress, and sensitivity to ascorbate

Judith Goncalves; Sophie Moog; Aurélie Morin; Geraldine Gentric; Sebastian Müller; Alexander P. Morrell; Katarina Kluckova; Theodora J. Stewart; Cynthia L. Andoniadou; Charlotte Lussey-Lepoutre; Paule Bénit; Alpesh Thakker; Lisa Vettore; Jennie Roberts; Raphaël Rodriguez; Fatima Mechta-Grigoriou; Anne Paule Gimenez-Roqueplo; Eric Letouzé; Daniel A. Tennant; Judith Favier

doi:10.1158/0008-5472.CAN-20-2936

Loss of sdhb promotes dysregulated iron homeostasis, oxidative stress, and sensitivity to ascorbate

Judith Goncalves, Sophie Moog, Aurélie Morin, Geraldine Gentric, Sebastian Müller, Alexander P. Morrell, Katarina Kluckova, Theodora J. Stewart, Cynthia L. Andoniadou, Charlotte Lussey-Lepoutre, Paule Bénit, Alpesh Thakker, Lisa Vettore, Jennie Roberts, Raphaël Rodriguez, Fatima Mechta-Grigoriou, Anne Paule Gimenez-Roqueplo, Eric Letouzé, Daniel A. Tennant, Judith Favier^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

34 Citations (Scopus)

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.

Original language	English
Pages (from-to)	3480-3494
Number of pages	15
Journal	Cancer Research
Volume	81
Issue number	13
DOIs	https://doi.org/10.1158/0008-5472.CAN-20-2936
Publication status	Published - 1 Jul 2021

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10.1158/0008-5472.CAN-20-2936

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Goncalves, J., Moog, S., Morin, A., Gentric, G., Müller, S., Morrell, A. P., Kluckova, K., Stewart, T. J., Andoniadou, C. L., Lussey-Lepoutre, C., Bénit, P., Thakker, A., Vettore, L., Roberts, J., Rodriguez, R., Mechta-Grigoriou, F., Gimenez-Roqueplo, A. P., Letouzé, E., Tennant, D. A., & Favier, J. (2021). Loss of sdhb promotes dysregulated iron homeostasis, oxidative stress, and sensitivity to ascorbate. Cancer Research, 81(13), 3480-3494. https://doi.org/10.1158/0008-5472.CAN-20-2936

@article{661c592cdf4c415c8e1fc5caa5b2b2e3,

title = "Loss of sdhb promotes dysregulated iron homeostasis, oxidative stress, and sensitivity to ascorbate",

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. ",

author = "Judith Goncalves and Sophie Moog and Aur{\'e}lie Morin and Geraldine Gentric and Sebastian M{\"u}ller and Morrell, {Alexander P.} and Katarina Kluckova and Stewart, {Theodora J.} and Andoniadou, {Cynthia L.} and Charlotte Lussey-Lepoutre and Paule B{\'e}nit and Alpesh Thakker and Lisa Vettore and Jennie Roberts and Rapha{\"e}l Rodriguez and Fatima Mechta-Grigoriou and Gimenez-Roqueplo, {Anne Paule} and Eric Letouz{\'e} and Tennant, {Daniel A.} and Judith Favier",

note = "Funding Information: K. Kluckova reports grants from The Paradifference Foundation during the conduct of the study. A. Thakker reports grants and other support from Paradifference Foundation during the conduct of the study. L. Vettore reports grants from Cancer Research UK during the conduct of the study. D.A. Tennant reports grants from The Paradifference Foundation and grants from Cancer Research UK during the conduct of the study. No disclosures were reported by the other authors. Funding Information: The authors thank all members of the Genetics Department, Biological Resources Center and Tumor Bank Platform, H{\^o}pital Europ{\'e}en Georges Pompidou (BB-0033– 00063), and the Metabolic Tracer Analysis Core (MTAC) at the University of Birmingham for access to their technology platform, as well as the London Metal-lomics Facility funded by the Wellcome Trust (grant reference 202902/Z/16/Z). We thank Dr Stijn J.M. Van Malderen for assistance with shift correction. This work was supported by The Plan Cancer, Epig{\'e}n{\'e}tique et Cancer (EPIG201303 METABEPIC), The Paradifference Foundation, la Ligue Contre le Cancer (Equipe Labellis{\'e}e) and the Cancer Research for Personalized Medicine - CARPEM project (Site de Recherche Int{\'e}gr{\'e}sur le Cancer - SIRIC). The London Metallomics Facility is funded by the Wellcome trust (grant no 202902/Z/16/Z). S. Moog is the recipient of a fellowship from la Fondation pour la Recherche M{\'e}dicale. J. Goncalves is the recipient of a fellowship from la Ligue Nationale contre le Cancer. The R.R. research group is funded by the European Research Council (ERC) under the European Union{\textquoteright}s Horizon 2020 research and innovation programme (grant agreement no 647973), the Fondation Charles Defforey-Institut de France, and Ligue Contre le Cancer (Equipe Labellis{\'e}e). Publisher Copyright: {\textcopyright} 2021 American Association for Cancer Research. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = jul,

day = "1",

doi = "10.1158/0008-5472.CAN-20-2936",

language = "English",

volume = "81",

pages = "3480--3494",

journal = "Cancer Research",

issn = "0008-5472",

publisher = "American Association for Cancer Research",

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Goncalves, J, Moog, S, Morin, A, Gentric, G, Müller, S, Morrell, AP, Kluckova, K, Stewart, TJ, Andoniadou, CL, Lussey-Lepoutre, C, Bénit, P, Thakker, A, Vettore, L, Roberts, J, Rodriguez, R, Mechta-Grigoriou, F, Gimenez-Roqueplo, AP, Letouzé, E, Tennant, DA & Favier, J 2021, 'Loss of sdhb promotes dysregulated iron homeostasis, oxidative stress, and sensitivity to ascorbate', Cancer Research, vol. 81, no. 13, pp. 3480-3494. https://doi.org/10.1158/0008-5472.CAN-20-2936

TY - JOUR

T1 - Loss of sdhb promotes dysregulated iron homeostasis, oxidative stress, and sensitivity to ascorbate

AU - Goncalves, Judith

AU - Moog, Sophie

AU - Morin, Aurélie

AU - Gentric, Geraldine

AU - Müller, Sebastian

AU - Morrell, Alexander P.

AU - Kluckova, Katarina

AU - Stewart, Theodora J.

AU - Andoniadou, Cynthia L.

AU - Lussey-Lepoutre, Charlotte

AU - Bénit, Paule

AU - Thakker, Alpesh

AU - Vettore, Lisa

AU - Roberts, Jennie

AU - Rodriguez, Raphaël

AU - Mechta-Grigoriou, Fatima

AU - Gimenez-Roqueplo, Anne Paule

AU - Letouzé, Eric

AU - Tennant, Daniel A.

AU - Favier, Judith

N1 - Funding Information: K. Kluckova reports grants from The Paradifference Foundation during the conduct of the study. A. Thakker reports grants and other support from Paradifference Foundation during the conduct of the study. L. Vettore reports grants from Cancer Research UK during the conduct of the study. D.A. Tennant reports grants from The Paradifference Foundation and grants from Cancer Research UK during the conduct of the study. No disclosures were reported by the other authors. Funding Information: The authors thank all members of the Genetics Department, Biological Resources Center and Tumor Bank Platform, Hôpital Européen Georges Pompidou (BB-0033– 00063), and the Metabolic Tracer Analysis Core (MTAC) at the University of Birmingham for access to their technology platform, as well as the London Metal-lomics Facility funded by the Wellcome Trust (grant reference 202902/Z/16/Z). We thank Dr Stijn J.M. Van Malderen for assistance with shift correction. This work was supported by The Plan Cancer, Epigénétique et Cancer (EPIG201303 METABEPIC), The Paradifference Foundation, la Ligue Contre le Cancer (Equipe Labellisée) and the Cancer Research for Personalized Medicine - CARPEM project (Site de Recherche Intégrésur le Cancer - SIRIC). The London Metallomics Facility is funded by the Wellcome trust (grant no 202902/Z/16/Z). S. Moog is the recipient of a fellowship from la Fondation pour la Recherche Médicale. J. Goncalves is the recipient of a fellowship from la Ligue Nationale contre le Cancer. The R.R. research group is funded by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement no 647973), the Fondation Charles Defforey-Institut de France, and Ligue Contre le Cancer (Equipe Labellisée). Publisher Copyright: © 2021 American Association for Cancer Research. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/7/1

Y1 - 2021/7/1

N2 - 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.

AB - 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.

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U2 - 10.1158/0008-5472.CAN-20-2936

DO - 10.1158/0008-5472.CAN-20-2936

M3 - Article

C2 - 34127497

AN - SCOPUS:85109000951

SN - 0008-5472

VL - 81

SP - 3480

EP - 3494

JO - Cancer Research

JF - Cancer Research

IS - 13

ER -

Loss of sdhb promotes dysregulated iron homeostasis, oxidative stress, and sensitivity to ascorbate

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