TY - JOUR
T1 - The ROS/SUMO Axis Contributes to the Response of Acute Myeloid Leukemia Cells to Chemotherapeutic Drugs
AU - Bossis, Guillaume
AU - Sarry, Jean Emmanuel
AU - Kifagi, Chamseddine
AU - Ristic, Marko
AU - Saland, Estelle
AU - Vergez, François
AU - Salem, Tamara
AU - Boutzen, Héléna
AU - Baik, Hayeon
AU - Brockly, Frédérique
AU - Pelegrin, Mireia
AU - Kaoma, Tony
AU - Vallar, Laurent
AU - Récher, Christian
AU - Manenti, Stéphane
AU - Piechaczyk, Marc
N1 - Funding Information:
M.P.’s laboratory is an “Equipe Labellisée” of the Ligue Nationale contre le Cancer. This work was also supported by the CNRS, the Association pour la Recherche sur le Cancer (ARC), the INCA, the G.A.E.L association, the Marie-Curie Initial Training Network from the European Union (290257-UPStream), the Fondation de France and the CRP-Santé (Luxembourg). We are grateful to Drs Hipskind and M.P.’s team for critical reading of the manuscript.
PY - 2014/6/26
Y1 - 2014/6/26
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84903388394&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2014.05.016
DO - 10.1016/j.celrep.2014.05.016
M3 - Article
C2 - 24910433
AN - SCOPUS:84903388394
SN - 2211-1247
VL - 7
SP - 1815
EP - 1823
JO - Cell Reports
JF - Cell Reports
IS - 6
ER -