title: PKCδ regulates death receptor 5 expression induced by PS-341 through ATF4-ATF3/CHOP axis in human lung cancer cells.
abstract: PS-341 (bortezomib), a proteasome inhibitor, has been approved for the treatment of multiple myeloma. Our previous work has shown that PS-341 induces death receptor 5 (DR5)-dependent apoptosis and enhances the TNF-related apoptosis-inducing ligand-induced apoptosis in human non-small cell lung cancer cells. However, the definite mechanism remains undefined. In the present study, we reveal that PKCδ and RSK2 mediate PS-341-induced DR5 upregulation, involving coactivation of endoplasmic reticulum (ER) stress. We discovered that PS-341 activated ER stress through elevating the expression of BiP, p-eIF2α, IRE1α, ATF4, ATF3, and CCAAT/enhancer-binding protein homologous protein (CHOP). Further study showed that DR5 upregulation was dependent on ATF4, ATF3, and CHOP expression. Silencing either one of the ATF4, ATF3, and CHOP expression decreased DR5 upregulation and subsequent apoptosis. We determined that ATF4 regulated ATF3 and CHOP expression. Thereafter, ATF3 and CHOP formed a complex and regulated DR5 expression. In addition, we discovered that the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and RSK2 were elevated after PS-341 treatment and inhibition of their phosphorylation using MAP-ERK kinase 1/2 inhibitor decreased the DR5 level, indicating that ERK/RSK2 signaling is involved in DR5 upregulation. Furthermore, we detected the cleavage of PKCδ, and the blockage of PKCδ expression cut down DR5 upregulation and apoptosis. Importantly, knockdown of PKCδ expression decreased the induction of ER stress and the phosphorylation of ERK1/2 and RSK2, suggesting that PKCδ regulates DR5 expression through ERK/RSK2 signaling and ATF4-CHOP/ATF3 axis. Collectively, we show that PS-341 induces PKCδ-dependent DR5 expression through activation of ERK/RSK2 and ER stress signaling pathway.
authors: Shandong University School of Life Sciences, Room 103, South Building, 27 Shanda South Road, Jinan, Shandong 250100, China.
authors: Linyan
authors: L
authors: Xu
authors: Ling
authors: L
authors: Su
authors: Xiangguo
authors: X
authors: Liu
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism*; D051701:Activating Transcription Factor 4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000069286:Bortezomib; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D051745:Protein Kinase C-delta / Q000378:metabolism*; D011719:Pyrazines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D013997:Time Factors; D051742:Transcription Factor CHOP / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C490449:ATF3 protein, human; C497109:ATF4 protein, human; D051700:Activating Transcription Factor 3; D001897:Boronic Acids; D011719:Pyrazines; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; D000069286:Bortezomib; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3; D051745:Protein Kinase C-delta; D048049:Extracellular Signal-Regulated MAP Kinases; D020169:Caspases