Tunicamycin (TN), one of the endoplasmic reticulum stress inducers, has been reported to inhibit
tumor cell growth and exhibit anticarcinogenic activity. However, the mechanism by which TN initiates apoptosis remains poorly understood. In the present study, we investigated the effect of TN on the apoptotic pathway in U937 cells. We show that TN induces apoptosis in association with
caspase-3 activation, generation of
reactive oxygen species (ROS), and downregulation of
survivin expression.
P38 MAPK (
mitogen-activated protein kinase) and the generation of ROS signaling pathway play crucial roles in TN-induced apoptosis in U937 cells. We hypothesized that TN-induced activation of
p38 MAPK signaling pathway is responsible for cell death. To test this hypothesis, we selectively inhibited MAPK during treatment with TN. Our data demonstrated that inhibitor of p38 (SB), but not ERK (PD) or JNK (SP), partially maintained apoptosis during treatment with TN. Pre-treatment with NAC and GSH markedly prevented cell death, suggesting a role for ROS in this process. Ectopic expression of
survivin in U937 cells attenuated TN-induced apoptosis by suppression of
caspase-3 cleavage, mitochondrial membrane potential, and
cytochrome c release in U937 cells. Taken together, our results show that TN modulates multiple components of the apoptotic response of human
leukemia cells and raise the possibility of a novel therapeutic strategy for
hematological malignancies.