title: PERK/CHOP contributes to the CGK733-induced vesicular calcium sequestration which is accompanied by non-apoptotic cell death.
abstract: Calcium ions (Ca(2+)) are indispensable for the physiology of organisms and the molecular regulation of cells. We observed that CGK733, a synthetic chemical substance, induced non-apoptotic cell death and stimulated reversible calcium sequestration by vesicles in pancreatic cancer cells. The endoplasmic reticulum (ER) stress eukaryotic translation initiation factor 2-alpha kinase 3/C/EBP homologous protein (PERK/CHOP) signaling pathway was shown to be activated by treatment with CGK733. Ionomycin, an ER stress drug and calcium ionophore, can activate PERK/CHOP signaling and accelerate CGK733-induced calcium sequestration. Knockdown of CHOP diminished CGK733-induced vesicular calcium sequestration, but had no effects on the cell death. Proteomic analysis demonstrated that the ER-located calcium-binding proteins, calumenin and protein S100-A11, were altered in CGK733-treated cells compared to non-treated controls. Our study reveals that CGK733-induced intracellular calcium sequestration is correlated with the PERK/CHOP signaling pathway and may also be involved in the dysregulations of calcium-binding proteins.
authors.affiliation: Department of Biochemistry and Functional Proteomics, Yamguchi University Graduate School of Medicine, Ube, Japan.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Functional Proteomics, Yamguchi University Graduate School of Medicine, Ube, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kuramitsu
authors.affiliation: Department of Biochemistry and Functional Proteomics, Yamguchi University Graduate School of Medicine, Ube, Japan.
authors.forename: Byron
authors.initials: B
authors.lastname: Baron
authors.affiliation: Department of Biochemistry and Functional Proteomics, Yamguchi University Graduate School of Medicine, Ube, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Kitagawa
authors.affiliation: Department of Biochemistry and Functional Proteomics, Yamguchi University Graduate School of Medicine, Ube, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Akada
authors.affiliation: Department of Biochemistry and Functional Proteomics, Yamguchi University Graduate School of Medicine, Ube, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tokuda
authors.affiliation: Department of Pathology, Yamguchi University Graduate School of Medicine, Ube, Japan.
authors.forename: Dan
authors.initials: D
authors.lastname: Cui
authors.affiliation: Department of Biochemistry and Functional Proteomics, Yamguchi University Graduate School of Medicine, Ube, Japan.|Centre of Clinical Laboratories in Tokuyama Medical Association Hospital, Shunan, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Nakamura
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D044482:Benzeneacetamides / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D061207:Calcium Ionophores / Q000494:pharmacology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D040901:Proteomics / Q000379:methods; D034622:RNA Interference; D009418:S100 Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D044482:Benzeneacetamides; C510527:CALU protein, human; C512273:CGK 733; D061207:Calcium Ionophores; D002135:Calcium-Binding Proteins; C497249:DDIT3 protein, human; D009418:S100 Proteins; C072337:S100A11 protein, human; D051742:Transcription Factor CHOP; C460640:EIF2AK3 protein, human; D019892:eIF-2 Kinase; D013890:Thiourea; D002118:Calcium
keywords: CGK733; ER stress; PERK/CHOP; calcium sequestration; non-apoptotic death