Oncotarget

Research Papers:

Dimethyl fumarate is highly cytotoxic in KRAS mutated cancer cells but spares non-tumorigenic cells

Nathaniel Edward Bennett Saidu, Marie Bretagne, Audrey Lupo Mansuet, Pierre-Alexandre Just, Karen Leroy, Olivier Cerles, Sandrine Chouzenoux, Carole Nicco, Diane Damotte, Marco Alifano, Bruno Borghese, François Goldwasser, Frédéric Batteux and Jérôme Alexandre _

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Oncotarget. 2018; 9:9088-9099. https://doi.org/10.18632/oncotarget.24144

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Abstract

Nathaniel Edward Bennett Saidu1, Marie Bretagne1, Audrey Lupo Mansuet2, Pierre-Alexandre Just2, Karen Leroy1,3, Olivier Cerles1, Sandrine Chouzenoux1, Carole Nicco1, Diane Damotte2, Marco Alifano4, Bruno Borghese5, François Goldwasser1,6, Frédéric Batteux1,7 and Jérôme Alexandre1,6

1Paris Descartes University, Sorbonne Paris Cité, INSERM U1016, Cochin Institute, CARPEM, Paris, France

2Department of Pathology, Cochin Hospital, AP-HP, Paris, France

3Department of Genetics and Molecular Biology, Cochin Hospital, AP-HP, Paris, France

4Department of Thoracic surgery, Cochin Hospital, AP-HP, Paris, France

5Department of Gynecologic Surgery, Cochin Hospital, AP-HP, Paris, France

6Department of Medical Oncology, Cochin Hospital, AP-HP, Paris, France

7Department of Immunology, Cochin Hospital, AP-HP, Paris, France

Correspondence to:

Jérôme Alexandre, email: jerome.alexandre@aphp.fr

Keywords: KRAS mutation; NRF2; DJ-1; primary cancer cells; non-tumorigenic cells

Received: August 29, 2017     Accepted: January 02, 2018     Published: January 10, 2018

ABSTRACT

KRAS mutation, one of the most common molecular alterations observed in adult carcinomas, was reported to activate the anti-oxidant program driven by the transcription factor NRF2 (Nuclear factor-erythroid 2-related factor 2). We previously observed that the antitumoral effect of Dimethyl fumarate (DMF) is dependent of NRF2 pathway inhibition. We used in vitro methods to examine the effect of DMF on cell death and the activation of the NRF2/DJ-1 antioxidant pathway. We report here that DMF is preferentially cytotoxic against KRAS mutated cancer cells. This effect was observed in patient-derived cancer cell lines harbouring a G12V KRAS mutation, compared with cell lines without such a mutation. In addition, KRAS*G12V over-expression in the human Caco-2 colon cancer cell line significantly promoted DMF-induced cell death, as well as DMF-induced- reactive oxygen species (ROS) formation and -glutathione (GSH) depletion. Moreover, in contrast to malignant cells, our data confirms that the same concentration of DMF has no significant cytotoxic effects on non-tumorigenic human ARPE-19 retinal epithelial, murine 3T3 fibroblasts and primary mice bone marrow cells; but is rather associated with NRF2 activation, decreased ROS and increased GSH levels. Furthermore, DJ-1 down-regulation experiments showed that this protein does not play a protective role against NRF2 in non-tumorigenic cells, as it does in malignant ones. This, interestingly, could be at the root of the differential effect of DMF observed between malignant and non-tumorigenic cells. Our results suggest for the first time that the dependence on NRF2 observed in mutated KRAS malignant cells makes them more sensitive to the cytotoxic effect of DMF, which thus opens up new prospects for the therapeutic applications of DMF.


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