Bossis Guillaume, Sarry Jean-Emmanuel, Kifagi Chamseddine, Ristic Marko, Saland Estelle, Vergez François, Salem Tamara, Boutzen Héléna, Baik Hayeon, Brockly Frédérique, Pelegrin Mireia, Kaoma Tony, Vallar Laurent, Récher Christian, Manenti Stéphane, Piechaczyk Marc
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.
Cancer Research Center of Toulouse, Inserm U1037, CNRS Equipe Labellisée 5294, Université Toulouse III, CHU Purpan, 31059 Toulouse, France.
Cell Rep. 2014 Jun 26;7(6):1815-23. doi: 10.1016/j.celrep.2014.05.016. Epub 2014 Jun 5.
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.
用于治疗急性髓系白血病（AML）的化疗药物被认为是通过产生DNA双链断裂来诱导癌细胞死亡的。在此，我们报告其早期效应之一是类泛素蛋白SUMO与其靶标的缀合丧失，这是通过活性氧（ROS）依赖性抑制SUMO缀合酶实现的。去SUMO化修饰调节特定基因的表达，如促凋亡基因DDIT3，并有助于在化疗敏感的AML中诱导凋亡。相比之下，化疗药物不会在化疗耐药细胞中激活ROS/SUMO轴。然而，促氧化剂或漆树酸对SUMO途径的抑制可恢复化疗耐药细胞系和患者样本（包括白血病干细胞）中DDIT3蛋白的表达及凋亡。最后，抑制SUMO途径可减少移植AML细胞的小鼠体内肿瘤的生长。因此，靶向ROS/SUMO轴可能构成对传统化疗耐药的AML患者的一种治疗策略。
