Restoration of SHIP-1 activity in human leukemic cells modifies NF-κB activation pathway and cellular survival upon oxidative stress

Nuclear factor-kappa B (NF-κB) is an important prosurvival transcription factor activated in response to a large array of external stimuli, including reactive oxygen species (ROS). Previous works have shown that NF-κB activation by ROS involved tyrosine phosphorylation of the inhibitor IκBα through an IκB kinase (IKK)-independent mechanism. In the present work, we investigated with more details NF-κB redox regulation in human leukemic cells. By using different cell lines (CEM, Jurkat and the subclone Jurkat JR), we clearly showed that NF-κB activation by hydrogen peroxide (H2O2) is cell-type dependent: it activates NF-κB through tyrosine phosphorylation of IκBα in Jurkat cells, whereas it induces an IKK-mediated IκBα phosphorylation on S32 and 36 in CEM and Jurkat JR cells. We showed that this H2O2-induced IKK activation in CEM and Jurkat JR cells is mediated by SH2-containing inositol 5′-phosphatase 1 (SHIP-1), a lipid phosphatase that is absent in Jurkat cells. Indeed, the complementation of SHIP-1 in Jurkat cells made them shift to an IKK-dependent mechanism upon oxidative stress stimulation. We also showed that Jurkat cells expressing SHIP-1 are more resistant to H2O2-induced apoptosis than the parental cells, suggesting that SHIP-1 has an important role in leukemic cell responses to ROS in terms of signal transduction pathways and apoptosis resistance, which can be of interest in improving ROS-mediated chemotherapies.