title: Tunicamycin promotes apoptosis in leukemia cells through ROS generation and downregulation of survivin expression.
abstract: 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.
authors.affiliation: Department of Molecular Biology and Immunology, Kosin University College of Medicine, 265 Gamcheon-ro, Seo-gu, Busan, 602-702, Korea.
authors.forename: Eun Jin
authors.initials: EJ
authors.lastname: Lim
authors.forename: Jeonghoon
authors.initials: J
authors.lastname: Heo
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Kim
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D059865:Endoplasmic Reticulum Stress; D005786:Gene Expression Regulation; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D007938:Leukemia / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000077022:Survivin; D014415:Tunicamycin / Q000494:pharmacology*; D020298:U937 Cells
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D000077022:Survivin; D014415:Tunicamycin; D053148:Caspase 3