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 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 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 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-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.
Highlights
Dimethyl fumarate (DMF) is a derivative of fumaric acid registered for the treatment of relapsing forms of multiple sclerosis and psoriasis
The data presented in this report supports the antitumor effect of DMF and discloses the molecular mechanism model for DMFinduced cancer cell death involving the relative depletion of NRF2 antioxidant system and increased ROS production
DMF is well known for its immunomodulatory effects and has recently been approved for the treatment of psoriasis and relapsing-remitting multiple sclerosis [1,2,3]
Summary
Dimethyl fumarate (DMF) is a derivative of fumaric acid registered for the treatment of relapsing forms of multiple sclerosis and psoriasis (http://www.fda.gov; refs. 1–3). Dimethyl fumarate (DMF) is a derivative of fumaric acid registered for the treatment of relapsing forms of multiple sclerosis and psoriasis NRF2 is a ubiquitously expressed basic leucine zipper transcription factor [7,8,9]. It is a "Master redox switch" as it is known to induce cytoprotective genes that render protection of cells from oxidative stress NRF2 is held in the cytoplasm as an inactive complex bound to Kelch-like ECH-associated protein 1 (KEAP1), a repressor mole-. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).
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