The monoclonal antibody 225 activates caspase-8 and induces apoptosis through a tumor necrosis factor receptor family-independent pathway
The monoclonal antibody 225 activates caspase-8 and induces apoptosis through a tumor necrosis factor receptor family-independent pathway
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DOI：
10.1038/sj.onc.1204490
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发表时间：
2001-06-21
期刊：
影响因子：
8
通讯作者：
Fan, Z
中科院分区：
文献类型：
--
作者：
Liu, BL;Fan, Z
我们曾报道抗表皮生长因子(EGF)受体单抗(MAb225)可诱导DIFI结肠癌细胞发生凋亡，并伴随着caspase-8和caspase-9两个凋亡启动子的激活。本研究发现，caspase-8特异性抑制剂z-IETD-fmk预处理DiFi细胞，而caspase-9特异性抑制剂z-Lehd-fmk不能抑制mAb225诱导的细胞凋亡，提示caspase-8在启动mAb225诱导的细胞凋亡中起重要作用。由于caspase-8主要由肿瘤坏死因子受体家族的成员如Fas、肿瘤坏死因子受体-1(TNFR1)或肿瘤坏死因子相关的凋亡诱导配体受体(TRAIL)激活，因此我们研究了mAb225是否通过调节这些已知途径中的一个或多个来激活caspase-8，使DIFI细胞暴露于肿瘤坏死因子α或TRAIL而激活caspase-8并诱导细胞凋亡。肿瘤坏死因子受体拮抗剂单抗或TRAIL诱骗受体分别抑制caspase-8的激活和随后由肿瘤坏死因子α或TRAIL诱导的细胞凋亡。但TNFR1拮抗型mAb和TRAIL诱骗受体均不抑制mAb225诱导的DIFI细胞caspase-8激活和凋亡，DIFI细胞表达可检测到的Fas，但对Fas激动型mAbCH-II不敏感，Fas拮抗型mAb(ZB-4)抑制Fas激动型mAbCH-11诱导的Jurkat T-白血病细胞caspase-8激活和凋亡(作为阳性对照)，但对mAb225诱导的caspase-8激活和DiFi细胞凋亡无影响。综上所述，我们的结果表明，mAb225不与这些已知的死亡受体途径相互作用或调节，因此有必要探索mAb225激活caspase-8并触发DiFi细胞凋亡的新机制。
We previously reported that the anti-epidermal growth factor (EGF) receptor monoclonal antibody (mAb) 225 induces DiFi colon cancer cells to undergo apoptosis, and this apoptosis was accompanied by activation of the two apoptosis initiation caspases, caspase-8 and caspase-9, In the current study, we found that pretreatment of DiFi cells with the caspase-8-specific inhibitor z-IETD-fmk but not pretreatment with the caspase-9-specific inhibitor z-LEHD-fmk inhibited mAb 225-induced apoptosis, indicating that caspase-8 plays an essential role in initiating mAb 225-induced apoptosis, Because caspase-8 is activated primarily by the members of the tumor necrosis factor (TNF) receptor family, such as Fas, TNF receptor-1 (TNFR1), or receptors for TNF-related apoptosis-inducing ligand (TRAIL), we investigated whether mAb 225 activated caspase-8 by regulating one or more of these known pathways, Exposure of DiFi cells to TNF alpha or TRAIL activated caspase-8 and induced apoptosis in the cells. A TNFR1-antagonistic mAb or a TRAIL decoy receptor inhibited the activation of caspase-8 and the subsequent apoptosis induced by TNF alpha or TRAIL, respectively, in the cells. However, neither the TNFR1-antagonistic mAb nor the TRAIL decoy receptor inhibited mAb 225-induced activation of caspase-8 and apoptosis in DiFi cells, DiFi cells express detectable level of Fas but are not sensitive to the treatment by the Fas-agonistic mAb CH-II, A Fas-antagonistic mAb (ZB-4) inhibited the Fas-agonistic mAb CH-ll-induced caspase-8 activation and apoptosis in Jurkat T-leukemic cells (used as positive control), but had no effect on mAb 225-induced activation of caspase-8 and apoptosis in DiFi cells. Taken together, our results suggest that mAb 225 does not interact with or regulate these known death receptor pathways, An exploration is therefore warranted for a novel mechanism by which mAb 225 activates caspase-8 and triggers apoptosis in DiFi cells.