Role of an endoplasmic reticulum Ca2+-independent phospholipase A2 in cisplatin-induced renal cell apoptosis
Role of an endoplasmic reticulum Ca2+-independent phospholipase A2 in cisplatin-induced renal cell apoptosis
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DOI：
10.1124/jpet.103.060541
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发表时间：
2004-03-01
影响因子：
3.5
通讯作者：
Schnellmann, RG
中科院分区：
文献类型：
--
作者：
Cummings, BS;McHowat, J;Schnellmann, RG
最近的研究表明，兔肾近端小管细胞（RPTC）表达一种新的钙离子非依赖性磷脂酶A（2）（iPLA（2）），其活性定位于内质网（ER-iPLA（2）），与VIB组PLA（2）相似。在这项研究中，检测了VIB组PLA 2的表达，并确定了ER-iPLA（2）在顺铂诱导的细胞凋亡中的作用。顺铂诱导的时间和浓度依赖性RPTC细胞凋亡的p53核定位，膜联蛋白V染色，半胱天冬酶3活性，染色质凝聚。用溴烯醇内酯（5 μ M）抑制ER-iPLA（2）可使顺铂诱导的膜联蛋白V结合减少40%，染色质浓缩减少55%，半胱天冬酶3活性减少42%，但对p53核定位没有影响。用蛋白激酶C刺激剂佛波醇12-肉豆蔻酸酯13-乙酸酯处理RPTC使ER-iPLA（2）的活性增加2倍，并增加顺铂诱导的RPTC凋亡。这些研究表明，VIB族PLA（2）在RPTC中表达，并表明RPTC ER-iPLA（2）是VIB族PLA（2）的兔同源物。这些数据还表明，ER-iPLA（2）在p53下游和caspase 3上游发挥作用，介导顺铂诱导的RPTC凋亡。最后，ER-iPLA（2）似乎受蛋白激酶C调节。
It has been demonstrated recently that rabbit renal proximal tubule cells (RPTC) express a novel Ca(2+)-independent phospholipase A(2) (iPLA(2)) whose activity localizes to the endoplasmic reticulum (ER-iPLA(2)) and is similar to group VIB PLA(2). In this study, the expression of group VIB PLA2 was examined and the role of ER-iPLA(2) in cisplatin-induced apoptosis was determined. Cisplatin induced both time- and concentration-dependent RPTC apoptosis as determined by p53 nuclear localization, annexin V staining, caspase 3 activity, and chromatin condensation. Inhibition of ER-iPLA(2) with bromoenol lactone (5 muM) reduced cisplatin-induced annexin V binding 40%, chromatin condensation 55%, and caspase 3 activity 42%, but had no effect on p53 nuclear localization. Treatment of RPTC with the protein kinase C stimulator phorbol 12-myristate 13-acetate increased the activity of ER-iPLA(2) 2-fold and increased cisplatin-induced RPTC apoptosis. These studies demonstrate that group VIB PLA(2) is expressed in RPTC and suggest that RPTC ER-iPLA(2) is the rabbit homolog of group VIB PLA(2). These data also demonstrate that ER-iPLA(2) acts downstream of p53 and upstream of caspase 3 to mediate cisplatin-induced RPTC apoptosis. Finally, ER-iPLA(2) seems to be regulated by protein kinase C.