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Dimethyl fumarate modulation of antioxidant response in cancer cells: therapeutic applications

RAS genes are among the most commonly mutated oncogenes in human cancers, where they have been shown to render resistance to chemotherapy. Hence, there is a current need for therapies targeting KRAS mutated tumors. The mutation of KRAS results in deregulated activation of signaling pathways involved in cell proliferation or survival. Thus, it was shown to induce the activation of nuclear factor erythroid 2 (NF-E2)-related factor 2 (NRF2), which itself controls the expression of a large number of antioxidant enzymes. Dimethyl fumarate (DMF) is a derivative of fumaric acid registered for the treatment of relapsing forms of multiple sclerosis and psoriasis. We previously described an antitumoral effect of DMF, which appeared dependent of the inhibition of the anti-oxidant program driven by NRF2 (Saidu et al. MCT, 2017). We have also shown the effect of DMF on cell death and the activation of the NRF2/DJ-1 antioxidant pathway according to KRAS status (Saidu et al., Oncotarget, 2017 – under review). Our data suggests the dependence on NRF2 observed in the mutated KRAS malignant cells makes them more sensitive to the cytotoxic effect of DMF. Moreover, in contrast to malignant cells, our data shows that the same concentration of DMF has no significant cytotoxic effects on non- malignant cells ; but is rather associated with NRF2 activation, decreased ROS and increased GSH levels. These results thus open up prospects for the therapeutic use of DMF. They however, also, open up questions such as: how does DMF affect A), NRF2-KEAP1/NRF2-DJ-1 protein interactions? B), other antioxidant proteins? C), are there other NRF2, KEAP1 and/or DJ-1 binding partners that are affected by DMF? To address these questions, we are currently employing tools/techniques such as kinomic analysis, MS, pull-down and co- immunoprecipitation assays ; results from which will broaden our understanding on how DMF modulates immune and antioxidant responses in different cancers.

Cancer ; Cell Death ; ROS ; DMF

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