title: Endoplasmic reticulum calcium pool depletion-induced apoptosis is coupled with activation of the death receptor 5 pathway.
abstract: Thapsigargin (TG), by inducing perturbations in cellular Ca(2+) homeostasis, has been shown to induce apoptosis. The molecular mechanisms of Ca(2+) perturbation-induced apoptosis are not fully understood. In this study, we demonstrate for the first time that TG-mediated perturbations in Ca(2+) homeostasis are coupled with activation of the death receptor 5 (DR5)-dependent apoptotic pathway in human cancer cells. TG selectively upregulated DR5 but had no effect on the expression of the other TRAIL receptor, DR4. TG also upregulated the expression of the DR5 ligand TRAIL (tumor necrosis factor-related apoptosis inducing ligand), albeit in a cell-type specific manner. TG-induced apoptosis has been shown to be associated with activation of the mitochondrial pathway. We found that TG upregulation of DR5 and TRAIL was coupled with caspase 8 activation and Bid cleavage, suggesting that the TG-regulated DR5 pathway could be linked to the mitochondrial pathway. TG enhanced not only DR5 mRNA stability but also increased induction of the DR5 genomic promoter-reporter gene. The TG-induced increase in DR5 expression appeared to occur as a consequence of TG-induced endoplasmic reticulum (ER) Ca(2+) pool depletion. Thus, we report our novel findings that ER Ca(2+) pool depletion-induced apoptotic signals are mediated, at least in part, via a DR5-dependent apoptotic pathway and there appears to be a cross-talk between the death receptor and mitochondrial pathways.
authors.affiliation: Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, New York, NY 13210, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: He
authors.forename: Dong Ik
authors.initials: DI
authors.lastname: Lee
authors.forename: Rong
authors.initials: R
authors.lastname: Rong
authors.forename: Myounghee
authors.initials: M
authors.lastname: Yu
authors.forename: Xiuquan
authors.initials: X
authors.lastname: Luo
authors.forename: Michael
authors.initials: M
authors.lastname: Klein
authors.forename: Wafik S
authors.initials: WS
authors.lastname: El-Deiry
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.forename: Arif
authors.initials: A
authors.lastname: Hussain
authors.forename: M Saeed
authors.initials: MS
authors.lastname: Sheikh
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D015152:Blotting, Northern; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053221:TNF-Related Apoptosis-Inducing Ligand; D019284:Thapsigargin / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D051017:Apoptosis Regulatory Proteins; D017931:DNA Primers; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D019284:Thapsigargin; D008156:Luciferases; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D002118:Calcium