Na/Ca Exchanger Overexpression Induces Endoplasmic Reticulum–Related Apoptosis and Caspase-12 Activation in Insulin-Releasing BRIN-BD11 Cells

Abstract

Ca2؉ 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. homeostasis that could, on the contrary, prevent the process of apoptosis that mediates, in part, ␤-cell autoimmune destruction in type 1 diabetes. NCX1.7 overexpression increased apoptosis induced by endoplasmic reticulum (ER) Ca

Initiation and execution of lipotoxic ER stress in pancreatic β-cells

“…ER Ca 2+ depletion activates the ER stress response in the case of thapsigargin and CPA, which inhibit the SERCA pump. Overexpression of the Na/Ca exchanger, a major Ca 2+ -extruding mechanism in β-cells, also depletes ER Ca 2+ stores with subsequent ER stress and caspase-12 activation in a rat β-cell line (Diaz-Horta et al, 2002). Cytokines also trigger ER stress in β-cells via nitric-oxide-mediated inhibition of SERCA (Cardozo et al, 2005).…”

Apoptosis of Insulin-Secreting Cells Induced by Endoplasmic Reticulum Stress Is Amplified by Overexpression of Group VIA Calcium-Independent Phospholipase A2 (iPLA2β) and Suppressed by Inhibition of iPLA2β

“…All three pathways result in activation of caspase-3 which is an executioner of apoptosis (24,44). ER stress-induced apoptosis has been reported to contribute to progressive β-cell death in the Akita diabetic mouse model (56) and to β-cell death induced by nitric oxide and the SERCA inhibitor thapsigargin (57,58), a known inducer of ER stress (23,54).…”

“…Three distinct recognized pathways for apoptosis include the (extrinsic) death receptor, the (intrinsic) mitochondrial, and the ER stress pathways (23,24,43,54,55). All three pathways result in activation of caspase-3 which is an executioner of apoptosis (24,44).…”

“…Several stimuli induce β-cell apoptosis (22) by incompletely understood mechanisms. Three currently recognized apoptotic signaling pathways are the extrinsic death receptor pathway, the intrinsic mitochondrial pathway, and the endoplasmic reticulum (ER) stress pathway (23,24).…”

Cell Death Mode Switch from Necrosis to Apoptosis in Brain

“…The ER accumulation of misfolded proteins causes cleavage and activation of IRE1a/b and caspase-12 (caspase-4 in human). 43,44) Activated IRE1a/b induces the oligomerization of TRAF-2, leading to apoptosis, as mentioned above. [45][46][47] Activated caspase-12, on the other hand, is linked to caspase-3 activation.…”