PKCδ Regulates Death Receptor 5 Expression Induced by PS-341 through ATF4–ATF3/CHOP Axis in Human Lung Cancer Cells

摘要: PS-341 (bortezomib), a proteasome inhibitor, has been approved for the treatment of multiple myeloma. Our previous work shown that induces death receptor 5 (DR5)-dependent apoptosis and enhances TNF-related apoptosis-inducing ligand-induced in human non-small cell lung cancer cells. However, definite mechanism remains undefined. In present study, we reveal PKCδ RSK2 mediate PS-341-induced DR5 upregulation, involving coactivation endoplasmic reticulum (ER) stress. We discovered activated ER stress through elevating expression BiP, p-eIF2α, IRE1α, ATF4, ATF3, CCAAT/enhancer-binding protein homologous (CHOP). Further study showed upregulation was dependent on CHOP expression. Silencing either one decreased subsequent apoptosis. determined ATF4 regulated ATF3 Thereafter, formed complex addition, phosphorylation extracellular signal-regulated kinase (ERK) 1/2 were elevated after inhibition their using MAP-ERK inhibitor level, indicating ERK/RSK2 signaling is involved upregulation. Furthermore, detected cleavage PKCδ, blockage cut down Importantly, knockdown induction ERK1/2 RSK2, suggesting regulates ATF4-CHOP/ATF3 axis. Collectively, show PKCδ-dependent activation pathway.