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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics

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Research Article

Dimethyl fumarate controls the NRF2/DJ-1 axis in cancer cells: therapeutic applications

Nathaniel Edward Bennett Saidu, Gaëlle Noé, Olivier Cerles, Luc Cabel, Niloufar Kavian-Tessler, Sandrine Chouzenoux, Mathilde Bahuaud, Christiane Chéreau, Carole Nicco, Karen Leroy, Bruno Borghese, Francois Goldwasser, Frédéric Batteux and Jerome Alexandre
Nathaniel Edward Bennett Saidu
Paris Descartes University, Sorbonne Paris Cité, INSERM U1016, Cochin Institute, CARPEM
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Gaëlle Noé
UMR8638 CNRS, Faculté de Pharmacie, Université Paris Descartes, PRES Sorbonne Paris Cité
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Olivier Cerles
Paris Descartes University, Sorbonne Paris Cité, INSERM U1016, Cochin Institute, CARPEM
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Luc Cabel
Paris Descartes University, Sorbonne Paris Cité, INSERM U1016, Cochin Institute, CARPEM
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Niloufar Kavian-Tessler
Paris Descartes University, Sorbonne Paris Cité, INSERM U1016, Cochin Institute, CARPEM
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Sandrine Chouzenoux
Paris Descartes University, Sorbonne Paris Cité, INSERM U1016, Cochin Institute, CARPEM
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Mathilde Bahuaud
Paris Descartes University, Sorbonne Paris Cité, INSERM U1016, Cochin Institute, CARPEM
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Christiane Chéreau
Paris Descartes University, Sorbonne Paris Cité, INSERM U1016, Cochin Institute, CARPEM
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Carole Nicco
Paris Descartes University, Sorbonne Paris Cité, INSERM U1016, Cochin Institute, CARPEM
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Karen Leroy
Paris Descartes University, Sorbonne Paris Cité, INSERM U1016, Cochin Institute, CARPEM
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Bruno Borghese
Department of gynecologic surgery, Cochin Hospital, AP-HP
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Francois Goldwasser
Department of medical oncology, Cochin hospital, AP-HP
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Frédéric Batteux
Department of immunology, Cochin hospital, AP-HP
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Jerome Alexandre
Department of medical oncology, Cochin Hospital, AP-HP
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  • For correspondence: jerome.alexandre@aphp.fr
DOI: 10.1158/1535-7163.MCT-16-0405
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Abstract

The transcription factor NRF2 (NFE2L2), regulates important antioxidant and cytoprotective genes. It enhances cancer cell proliferation and promotes chemoresistance in several cancers. Dimethyl fumarate (DMF) is known to promote NRF2 activity in non-cancer models. We combined in vitro and in vivo methods to examine the effect of DMF on cancer cell death and the activation of the NRF2 antioxidant pathway. We demonstrated that at lower concentrations (< 25 μM), DMF has a cytoprotective role through activation of the NRF2 antioxidant pathway. At higher concentrations, however (> 25 μM), DMF caused oxidative stress and subsequently cytotoxicity in several cancer cell lines. High DMF concentration decreases nuclear translocation of NRF2 and production of its downstream targets. The pro-oxidative and cytotoxic effects of high concentration of DMF were abrogated by over-expression of NRF2 in OVCAR3 cells, suggesting that DMF cytotoxicity is dependent of NRF2 depletion. High concentrations of DMF decreased the expression of DJ-1, a NRF2 protein stabiliser. Using DJ-1 siRNA and expression vector, we observed that the expression level of DJ-1 controls NRF2 activation, antoxidant defences and cell death in OVCAR3 cells. Finally, antitumoral effect of daily DMF (20 mg/kg) was also observed in vivo in two mice models of colon cancer. Taken together, these findings implicate the effect of DJ-1 on NRF2 in cancer development and identify DMF as a dose dependant modulator of both NRF2 and DJ-1, which may be useful in exploiting the therapeutic potential of these endogenous antioxidants.

  • Received June 22, 2016.
  • Revision received December 7, 2016.
  • Accepted December 7, 2016.
  • Copyright ©2017, American Association for Cancer Research.
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Published OnlineFirst January 9, 2017
doi: 10.1158/1535-7163.MCT-16-0405

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Dimethyl fumarate controls the NRF2/DJ-1 axis in cancer cells: therapeutic applications
Nathaniel Edward Bennett Saidu, Gaëlle Noé, Olivier Cerles, Luc Cabel, Niloufar Kavian-Tessler, Sandrine Chouzenoux, Mathilde Bahuaud, Christiane Chéreau, Carole Nicco, Karen Leroy, Bruno Borghese, Francois Goldwasser, Frédéric Batteux and Jerome Alexandre
Mol Cancer Ther January 9 2017 DOI: 10.1158/1535-7163.MCT-16-0405

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Dimethyl fumarate controls the NRF2/DJ-1 axis in cancer cells: therapeutic applications
Nathaniel Edward Bennett Saidu, Gaëlle Noé, Olivier Cerles, Luc Cabel, Niloufar Kavian-Tessler, Sandrine Chouzenoux, Mathilde Bahuaud, Christiane Chéreau, Carole Nicco, Karen Leroy, Bruno Borghese, Francois Goldwasser, Frédéric Batteux and Jerome Alexandre
Mol Cancer Ther January 9 2017 DOI: 10.1158/1535-7163.MCT-16-0405
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Copyright 2016 by the American Association for Cancer Research.

Molecular Cancer Therapeutics
eISSN: 1538-8514
ISSN: 1535-7163

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