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Cell Rep. 2014 Jun 26;7(6):1815-23. doi: 10.1016/j.celrep.2014.05.016. Epub 2014 Jun 5.

The ROS/SUMO axis contributes to the response of acute myeloid leukemia cells to chemotherapeutic drugs.

Author information

1
Equipe Labellisée Ligue contre le Cancer, Institut de Génétique Moléculaire de Montpellier, UMR 5535 CNRS, Université Montpellier 1, Université Montpellier 2, 1919 Route de Mende, 34293 Montpellier, France. Electronic address: guillaume.bossis@igmm.cnrs.fr.
2
Cancer Research Center of Toulouse, Inserm U1037, CNRS Equipe Labellisée 5294, Université Toulouse III, CHU Purpan, 31059 Toulouse, France.
3
Equipe Labellisée Ligue contre le Cancer, Institut de Génétique Moléculaire de Montpellier, UMR 5535 CNRS, Université Montpellier 1, Université Montpellier 2, 1919 Route de Mende, 34293 Montpellier, France.
4
Genomics Research Unit, Centre de Recherche Public de la Santé (CRP-Santé) 84, Val Fleuri 1526, Luxembourg.
5
Cancer Research Center of Toulouse, Inserm U1037, CNRS Equipe Labellisée 5294, Université Toulouse III, CHU Purpan, 31059 Toulouse, France; Département d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer Toulouse Oncopole, 1 Avenue Irène Joliot-Curie, 31059 Toulouse cedex, France.
6
Equipe Labellisée Ligue contre le Cancer, Institut de Génétique Moléculaire de Montpellier, UMR 5535 CNRS, Université Montpellier 1, Université Montpellier 2, 1919 Route de Mende, 34293 Montpellier, France. Electronic address: marc.piechaczyk@igmm.cnrs.fr.

Abstract

Chemotherapeutic drugs used in the treatment of acute myeloid leukemias (AMLs) are thought to induce cancer cell death through the generation of DNA double-strand breaks. Here, we report that one of their early effects is the loss of conjugation of the ubiquitin-like protein SUMO from its targets via reactive oxygen species (ROS)-dependent inhibition of the SUMO-conjugating enzymes. Desumoylation regulates the expression of specific genes, such as the proapoptotic gene DDIT3, and helps induce apoptosis in chemosensitive AMLs. In contrast, chemotherapeutics do not activate the ROS/SUMO axis in chemoresistant cells. However, pro-oxidants or inhibition of the SUMO pathway by anacardic acid restores DDIT3 expression and apoptosis in chemoresistant cell lines and patient samples, including leukemic stem cells. Finally, inhibition of the SUMO pathway decreases tumor growth in mice xenografted with AML cells. Thus, targeting the ROS/SUMO axis might constitute a therapeutic strategy for AML patients resistant to conventional chemotherapies.

PMID:
24910433
DOI:
10.1016/j.celrep.2014.05.016
[Indexed for MEDLINE]
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