Hydrogen peroxide activation of ERK5 confers resistance to Jurkat cells against apoptosis induced by the extrinsic pathway

• H2O2 attenuates FasL-induced Jurkat cell apoptosis.
• ERK5 activation mediates this anti-apoptotic effect.
• Inhibition of ERK5 together with chemotherapeutic drugs should enhance cell kill.

Reactive oxygen species (ROS) including hydrogen peroxide (H2O2) exhibit both pro-survival and pro-death signaling in leukemic cells. We examined the effect of exogenous H2O2 on Fas ligand (FasL) -induced apoptosis in Jurkat cells. H2O2 applied prior to (pre-conditioning) and during (post-conditioning) FasL stimulation attenuated early apoptosis through activation of EKR5. H2O2 increased the activated caspase-8 sequestered in the mitochondria thereby decreasing cell death through the extrinsic apoptotic pathway. In addition, inhibition of a protein tyrosine phosphatase likely explains the post-conditioning requirement for H2O2. Given that chemotherapeutic agents used for the treatment of acute lymphoblastic leukemia are thought to work partly through production of ROS, a simultaneous inhibition of the ERK5 pathway may abrogate the ROS-initiated pro-survival signaling for an enhanced cell kill.