title: Dimethyl Fumarate Controls the NRF2/DJ-1 Axis in Cancer Cells: Therapeutic Applications.
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 noncancer models. We combinedin vitroandin vivomethods 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 μmol/L), DMF has a cytoprotective role through activation of the NRF2 antioxidant pathway. At higher concentrations, however (>25 μmol/L), 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 overexpression 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 stabilizer. Using DJ-1 siRNA and expression vector, we observed that the expression level of DJ-1 controls NRF2 activation, antioxidant defenses, and cell death in OVCAR3 cells. Finally, antitumoral effect of daily DMF (20 mg/kg) was also observed invivoin 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-dependent modulator of both NRF2 and DJ-1, which may be useful in exploiting the therapeutic potential of these endogenous antioxidants.Mol Cancer Ther; 16(3); 529-39. ©2017 AACR.
authors.affiliation: Paris Descartes University, Sorbonne Paris Cité, INSERM U1016, Cochin Institute, CARPEM, Paris, France.
authors.forename: Nathaniel Edward Bennett
authors.initials: NE
authors.lastname: Saidu
authors.affiliation: UMR8638 CNRS, Faculté de Pharmacie, Université Paris Descartes, PRES Sorbonne Paris Cité, Paris, France.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Noé
authors.affiliation: Paris Descartes University, Sorbonne Paris Cité, INSERM U1016, Cochin Institute, CARPEM, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Cerles
authors.affiliation: Paris Descartes University, Sorbonne Paris Cité, INSERM U1016, Cochin Institute, CARPEM, Paris, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Cabel
authors.affiliation: Paris Descartes University, Sorbonne Paris Cité, INSERM U1016, Cochin Institute, CARPEM, Paris, France.
authors.forename: Niloufar
authors.initials: N
authors.lastname: Kavian-Tessler
authors.affiliation: Paris Descartes University, Sorbonne Paris Cité, INSERM U1016, Cochin Institute, CARPEM, Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Chouzenoux
authors.affiliation: Paris Descartes University, Sorbonne Paris Cité, INSERM U1016, Cochin Institute, CARPEM, Paris, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Bahuaud
authors.affiliation: Paris Descartes University, Sorbonne Paris Cité, INSERM U1016, Cochin Institute, CARPEM, Paris, France.
authors.forename: Christiane
authors.initials: C
authors.lastname: Chéreau
authors.affiliation: Paris Descartes University, Sorbonne Paris Cité, INSERM U1016, Cochin Institute, CARPEM, Paris, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Nicco
authors.affiliation: Paris Descartes University, Sorbonne Paris Cité, INSERM U1016, Cochin Institute, CARPEM, Paris, France.|Department of Molecular Genetics, Cochin Hospital, AP-HP, Paris, France.
authors.forename: Karen
authors.initials: K
authors.lastname: Leroy
authors.affiliation: Department of Gynecologic Surgery, Cochin Hospital, AP-HP, Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Borghese
authors.affiliation: Paris Descartes University, Sorbonne Paris Cité, INSERM U1016, Cochin Institute, CARPEM, Paris, France.|Department of Medical Oncology, Cochin Hospital, AP-HP, Paris, France.
authors.forename: François
authors.initials: F
authors.lastname: Goldwasser
authors.affiliation: Paris Descartes University, Sorbonne Paris Cité, INSERM U1016, Cochin Institute, CARPEM, Paris, France.|Department of Immunology, Cochin Hospital, AP-HP, Paris, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Batteux
authors.affiliation: Paris Descartes University, Sorbonne Paris Cité, INSERM U1016, Cochin Institute, CARPEM, Paris, France. jerome.alexandre@aphp.fr.|Department of Medical Oncology, Cochin Hospital, AP-HP, Paris, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Alexandre
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000069462:Dimethyl Fumarate / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D000071617:Protein Deglycase DJ-1 / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; D000071617:Protein Deglycase DJ-1; D000069462:Dimethyl Fumarate; D005978:Glutathione