Roles of cytoplasmic Ca2+ and intracellular Ca2+ stores in induction and suppression of apoptosis in S49 cells.
The Ca2+-ATPase inhibitors, thapsigargin and cyclopiazonic acid, depleted intracellular Ca2+ stores, induced large increases in intracellular Ca2+ concentration, and caused apoptosis in S49 cells. Removal of extracellular Ca2+ augmented apoptosis due to thapsigargin, indicating that depletion of Ca2+ from intracellular stores is responsible for apoptosis with this agent. Overexpression of the apoptosis suppressor, Bcl-2, inhibited apoptosis due to thapsigargin but did not affect thapsigargin-induced Ca2+ signaling. Dexamethasone induced apoptosis, diminished the size of the endoplasmic reticulum Ca2+ pool, and caused a small elevation of intracellular Ca2+. However, this elevation was not due to Ca2+ influx because the increase was similar in the presence or absence of Ca2+ in the medium. Furthermore, in contrast to the results with thapsigargin, apoptosis due to dexamethasone was unchanged in a Ca2+-free medium. These results indicate that depletion of Ca2+ stores initiates a pathway leading to apoptosis. Elevations in cytoplasmic Ca2+ appears to play a lesser role than previously thought in the actions of Bcl-2 and glucocorticoids.
Bian
X
X
Laboratory of Cellular and Molecular Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Hughes
F M
FM
Huang
Y
Y
Cidlowski
J A
JA
Putney
J W
JW
D017209:Apoptosis / Q000502:physiology*; D002118:Calcium / Q000378:metabolism* / Q000502:physiology*; D002461:Cell Line, Transformed / Q000187:drug effects; D003593:Cytoplasm / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007425:Intracellular Membranes / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D019284:Thapsigargin / Q000494:pharmacology
D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D007211:Indoles; D019253:Proto-Oncogene Proteins c-bcl-2; D019284:Thapsigargin; D003907:Dexamethasone; D002118:Calcium; C000543:cyclopiazonic acid