Arsenic trioxide induces endoplasmic reticulum stress-related events in neutrophils.
We recently reported that the endoplasmic reticulum (ER)-induced cell pathway of apoptosis is operational in human neutrophils and that some ER stressors can accelerate this process. Recent data suggest that arsenic trioxide (As(2)O(3) or ATO), may also act as an ER stressor. The aims of the present study were to elucidate if other ER stress-related events occur in ATO-induced neutrophils, and to determine the role of caspase-4 in the proapoptotic activity of ATO. We found that ATO induced ubiquitination of proteins, and increased calcium concentration and gene expression of calcineurin in neutrophils. In addition to caspase-4, activities of caspase-3, -8 and -9 were increased by ATO. The processing of caspase-4 was reversed by a caspase-8 inhibitor, indicating that caspase-4 activation requires the action of upstream initiator components, questioning on the role of caspase-4 in ATO-induced ER stress-mediated cell apoptosis. Using caspase-4 deficient THP-1 cells, we demonstrated that the proapoptotic effect of ATO was similar to that of control caspase-4-positive cells. We conclude that ATO is an ER stressor that can induce cell apoptosis by a mechanism which does not require caspase-4. In addition, we conclude that caspase-4 activation in ATO-induced neutrophils could be involved in functions other than apoptosis.
Laboratoire de recherche en inflammation et physiologie des granulocytes, Université du Québec, INRS-Institut Armand-Frappier, Laval, Qc, Canada.
François
F
Binet
Sonia
S
Chiasson
Denis
D
Girard
D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals; D015153:Blotting, Western; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D053471:Caspases, Initiator / Q000378:metabolism; D002469:Cell Separation; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology; D010087:Oxides / Q000633:toxicity*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014451:Ubiquinone / Q000378:metabolism
D000970:Antineoplastic Agents; D001152:Arsenicals; D061945:Caspase Inhibitors; D010087:Oxides; D014451:Ubiquinone; D019703:Calcineurin; C093516:CASP4 protein, human; D020169:Caspases; D053471:Caspases, Initiator; D000077237:Arsenic Trioxide; D002118:Calcium