title: Arsenite-induced endoplasmic reticulum-dependent apoptosis through disturbance of calcium homeostasis in HBE cell line.
abstract: Calcium (Ca2+) is a ubiquitous cell signal responsible for multiple fundamental cellular functions, including apoptosis. Whether the homeostasis of Ca2+is involved in arsenite-induced apoptosis remains unclear. In this study, we observed that arsenite significantly elevated the intracellular Ca2+concentration in a dose- and time-dependent manner. By using the Ca2+-ATPase inhibitor, thapsigargin, and the inositol 1,4,5- trisphosphate receptors (IP3Rs) inhibitor, heparin, we further confirmed that the disturbance of endoplasmic reticulum (ER) Ca2+homeostasis caused Ca2+overload in the cells. Moreover, loss of ER Ca2+homeostasis also led to ER stress, mitochondrial dysfunction, and NF-κB activation. Importantly, pretreatment of cells with heparin remarkably attenuated the elevated cell apoptosis induced by arsenite, but inhibition of ER Ca2+uptake with thapsigargin exacerbated arsenite-induced cell damage significantly. Together, we demonstrated for the first time that arsenite disturbed the Ca2+homeostasis in ER, which subsequently led to ER stress, mitochondrial dysfunction, and NF-κB nuclear translocation, and thus consequently triggering cell apoptosis. Our findings indicate regulation of disrupted Ca2+homeostasis in ER may be a potential strategy for prevention of arsenite toxicity. © 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 197-216, 2017.
authors.affiliation: Department of Occupational and Environmental Health, West China School of Public Health, Sichuan University, Chengdu, Sichuan, People's Republic of China.|Department of Occupational and Environmental Health, School of Public Health and Management, Chongqing Medical University, Chongqing, People's Republic of China.
authors.forename: Chengzhi
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Occupational and Environmental Health, West China School of Public Health, Sichuan University, Chengdu, Sichuan, People's Republic of China.
authors.forename: Shiyan
authors.initials: S
authors.lastname: Gu
authors.affiliation: Department of Occupational and Environmental Health, West China School of Public Health, Sichuan University, Chengdu, Sichuan, People's Republic of China.|Department of Occupational and Environmental Health, School of Public Health and Management, Chongqing Medical University, Chongqing, People's Republic of China.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Occupational and Environmental Health, West China School of Public Health, Sichuan University, Chengdu, Sichuan, People's Republic of China.
authors.forename: Zunzhen
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D018053:Arsenites / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006493:Heparin / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000037:antagonists & inhibitors; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism
chemical_list: D018053:Arsenites; D053496:Inositol 1,4,5-Trisphosphate Receptors; D016328:NF-kappa B; D006493:Heparin; C015001:arsenite; D002118:Calcium
keywords: apoptosis; arsenite; calcium homeostasis; endoplasmic reticulum