Foghsgaard Lasse, Lademann Ulrik, Wissing Dorte, Poulsen Birgit, Jaattela Marja
Apoptosis Laboratory, Institute of Cancer Biology, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen, Denmark.
J Biol Chem. 2002 Oct 18;277(42):39499-506. doi: 10.1074/jbc.M206669200. Epub 2002 Aug 15.
Arachidonic acid (AA) generated by cytosolic phospholipase A2 (cPLA2) has been suggested to function as a second messenger in tumor necrosis factor (TNF)-induced death signaling. Here, we show that cathepsin B-like proteases are required for the TNF-induced AA release in transformed cells. Pharmaceutical inhibitors of cathepsin B blocked TNF-induced AA release in human breast (MCF-7S1) and cervix (ME-180as) carcinoma as well as murine fibrosarcoma (WEHI-S) cells. Furthermore, TNF-induced AA release was significantly reduced in cathepsin B-deficient immortalized murine embryonic fibroblasts. Employing cPLA2-deficient MCF-7S1 cells expressing ectopic cPLA2 or cPLA2-deficient immortalized murine embryonic fibroblasts, we showed that cPLA2 is dispensable for TNF-induced AA release and death in these cells. Furthermore, TNF-induced cathepsin B-dependent AA release could be dissociated from the cathepsin B-independent cell death in MCF-7S1 cells, whereas both events required cathepsin B activity in other cell lines tested. These data suggest that cathepsin B inhibitors may prove useful not only in the direct control of cell death but also in limiting the damage-associated inflammation.
由胞质磷脂酶A2（cPLA2）产生的花生四烯酸（AA）被认为在肿瘤坏死因子（TNF）诱导的死亡信号传导中作为第二信使发挥作用。在此，我们表明组织蛋白酶B样蛋白酶是TNF诱导的转化细胞中AA释放所必需的。组织蛋白酶B的药物抑制剂阻断了人乳腺癌（MCF-7S1）和宫颈癌（ME-180as）以及小鼠纤维肉瘤（WEHI-S）细胞中TNF诱导的AA释放。此外，在组织蛋白酶B缺陷的永生化小鼠胚胎成纤维细胞中，TNF诱导的AA释放显著减少。利用表达异位cPLA2的cPLA2缺陷型MCF-7S1细胞或cPLA2缺陷的永生化小鼠胚胎成纤维细胞，我们表明cPLA2对于这些细胞中TNF诱导的AA释放和死亡是可有可无的。此外，TNF诱导的组织蛋白酶B依赖性AA释放可以与MCF-7S1细胞中不依赖组织蛋白酶B的细胞死亡分离，而在其他测试的细胞系中这两个事件都需要组织蛋白酶B的活性。这些数据表明，组织蛋白酶B抑制剂可能不仅在直接控制细胞死亡方面有用，而且在限制与损伤相关的炎症方面也有用。
