Na/Ca exchanger overexpression induces endoplasmic reticulum-related apoptosis and caspase-12 activation in insulin-releasing BRIN-BD11 cells.
Ca(2+) may trigger programmed cell death (apoptosis) and regulate death-specific enzymes. Therefore, the development of strategies to control Ca(2+) homeostasis may represent a potential approach to prevent or enhance cell apoptosis. To test this hypothesis, the plasma membrane Na/Ca exchanger (NCX1.7 isoform) was stably overexpressed in insulin-secreting tumoral cells. NCX1.7 overexpression increased apoptosis induced by endoplasmic reticulum (ER) Ca(2+)-ATPase inhibitors, but not by agents increasing intracellular calcium concentration ([Ca(2+)](i)), through the opening of plasma membrane Ca(2+)-channels. NCX1.7 overexpression reduced the rise in [Ca(2+)](i) induced by all agents, depleted ER Ca(2+) stores, sensitized the cells to Ca(2+)-independent proapoptotic signaling pathways, and reduced cell proliferation by approximately 40%. ER Ca(2+) stores depletion was accompanied by the activation of the ER-specific caspase (caspase-12), and the activation was enhanced by ER Ca(2+)-ATPase inhibitors. Hence, Na/Ca exchanger overexpression, by depleting ER Ca(2+) stores, triggers the activation of caspase-12 and increases apoptotic cell death. By increasing apoptosis and decreasing cell proliferation, overexpression of Na/Ca exchanger may represent a new potential approach in cancer gene therapy. On the other hand, our results open the way to the development of new strategies to control cellular Ca(2+) homeostasis that could, on the contrary, prevent the process of apoptosis that mediates, in part, beta-cell autoimmune destruction in type 1 diabetes.
Diaz-Horta
Oscar
O
Laboratory of Pharmacology, Brussels University School of Medicine, Brussels, Belgium.
Kamagate
Adama
A
Herchuelz
André
A
Van Eylen
Françoise
F
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D053454:Caspase 12; D020169:Caspases / Q000378:metabolism*; D002455:Cell Division; D002460:Cell Line; D053938:DNA Fragmentation; D003922:Diabetes Mellitus, Type 1 / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000502:physiology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008856:Microscopy, Fluorescence; D051381:Rats; D019831:Sodium-Calcium Exchanger / Q000235:genetics*
D004791:Enzyme Inhibitors; D007328:Insulin; D019831:Sodium-Calcium Exchanger; C110374:sodium-calcium exchanger 1; C506444:CASP12 protein, human; C506443:Casp12 protein, rat; D053454:Caspase 12; D020169:Caspases; D000252:Calcium-Transporting ATPases; D002118:Calcium