Endoplasmic reticulum stress and alteration in calcium homeostasis are involved in cadmium-induced apoptosis.
Cadmium, a toxic environmental contaminant, exerts adverse effects on different cellular pathways such as cell proliferation, DNA damage and apoptosis. In particular, the modulation of Ca(2+) homeostasis seems to have an important role during Cd(2+) injury, but the precise assessment of Ca(2+) signalling still remains poorly understood. We used aequorin-based probes specifically directed to intracellular organelles to study Ca(2+) changes during cadmium injury. We observed that cadmium decreased agonist-evoked endoplasmic reticulum (ER) Ca(2+) signals and caused a 40% inhibition of sarcoplasmic-ER calcium ATPases activity. Moreover, time course experiments correlate morphological alterations, processing of xbp-1 mRNA and caspase-12 activation during cadmium administration. Finally, the time response of ER to cadmium injury was compared with that of mitochondria. In conclusion, we highlighted a novel pathway of cadmium-induced cell death triggered by ER stress and involving caspase-12. Mitochondria and ER pathways seemed to share common time courses and a parallel activation of caspase-12 and caspase-9 seemed likely to be involved in acute cadmium toxicity.
Biagioli
Marta
M
Laboratory of Cellular and Development Biology, Department of Biology, University of Pisa, Italy. biagioli@sissa.it
Pifferi
Simone
S
Ragghianti
Matilde
M
Bucci
Stefania
S
Rizzuto
Rosario
R
Pinton
Paolo
P
D000331:Aequorin / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001920:Bradykinin / Q000494:pharmacology; D002104:Cadmium / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D053454:Caspase 12 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D004789:Enzyme Activation; D006706:Homeostasis / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure; D041681:NIH 3T3 Cells; D017510:Protein Folding; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D000071717:X-Box Binding Protein 1
D004268:DNA-Binding Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; D002104:Cadmium; D000331:Aequorin; D045304:Cytochromes c; D053454:Caspase 12; D001920:Bradykinin; D002118:Calcium