Apoptosis of Insulin-Secreting Cells Induced by Endoplasmic Reticulum Stress Is Amplified by Overexpression of Group VIA Calcium-Independent Phospholipase A2 (iPLA2
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- 作者：Sasanka Ramanadham ; Fong-Fu Hsu ; Sheng Zhang ; Chun Jin ; Alan Bohrer ; Haowei Song ; Shunzhong Bao ; Zhongmin Ma ; and John Turk
- 刊名：Biochemistry
- 出版年：2004
- 出版时间：February 3, 2004
- 年：2004
- 卷：43
- 期：4
- 页码：918 - 930
- 全文大小：1164K
- 年卷期：v.43,no.4(February 3, 2004)
- ISSN：1520-4995
文摘
The death of insulin-secreting 
-cells that causes type I diabetes mellitus (DM) occurs in partby apoptosis, and apoptosis also contributes to progressive -cell dysfunction in type II DM. Recentreports indicate that ER stress-induced apoptosis contributes to -cell loss in diabetes. Agents that depleteER calcium levels induce -cell apoptosis by a process that is independent of increases in [Ca2+]i. Herewe report that the SERCA inhibitor thapsigargin induces apoptosis in INS-1 insulinoma cells and thatthis is inhibited by a bromoenol lactone (BEL) inhibitor of group VIA calcium-independent phospholipaseA2 (iPLA2). Overexpression of iPLA2 amplifies thapsigargin-induced apoptosis of INS-1 cells, andthis is also suppressed by BEL. The magnitude of thapsigargin-induced INS-1 cell apoptosis correlateswith the level of iPLA2 expression in various cell lines, and apoptosis is associated with stimulation ofiPLA2 activity, perinuclear accumulation of iPLA2 protein and activity, and caspase-3-catalyzed cleavageof full-length 84 kDa iPLA2 to a 62 kDa product that associates with nuclei. Thapsigargin also inducesceramide accumulation in INS-1 cells, and this response is amplified in cells that overexpress iPLA2.These findings indicate that iPLA2 participates in ER stress-induced apoptosis, a pathway that promotes-cell death in diabetes.
-cells that causes type I diabetes mellitus (DM) occurs in partby apoptosis, and apoptosis also contributes to progressive -cell dysfunction in type II DM. Recentreports indicate that ER stress-induced apoptosis contributes to -cell loss in diabetes. Agents that depleteER calcium levels induce -cell apoptosis by a process that is independent of increases in [Ca2+]i. Herewe report that the SERCA inhibitor thapsigargin induces apoptosis in INS-1 insulinoma cells and thatthis is inhibited by a bromoenol lactone (BEL) inhibitor of group VIA calcium-independent phospholipaseA2 (iPLA2). Overexpression of iPLA2 amplifies thapsigargin-induced apoptosis of INS-1 cells, andthis is also suppressed by BEL. The magnitude of thapsigargin-induced INS-1 cell apoptosis correlateswith the level of iPLA2 expression in various cell lines, and apoptosis is associated with stimulation ofiPLA2 activity, perinuclear accumulation of iPLA2 protein and activity, and caspase-3-catalyzed cleavageof full-length 84 kDa iPLA2 to a 62 kDa product that associates with nuclei. Thapsigargin also inducesceramide accumulation in INS-1 cells, and this response is amplified in cells that overexpress iPLA2.These findings indicate that iPLA2 participates in ER stress-induced apoptosis, a pathway that promotes-cell death in diabetes.