TRAIL signaling is mediated by DR4 in pancreatic tumor cells despite the expression of functional DR5
TRAIL signaling is mediated by DR4 in pancreatic tumor cells despite the expression of functional DR5
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DOI：
10.1007/s00109-010-0619-0
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发表时间：
2010-07-01
影响因子：
4.7
通讯作者：
Trauzold, Anna
中科院分区：
文献类型：
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作者：
Lemke, Johannes;Noack, Andreas;Trauzold, Anna
肿瘤坏死因子相关凋亡诱导配体（Tumor necrosis factor related apoptosis inducing ligand， TRAIL）和抗dr4 /TRAIL- r1和抗dr5 /TRAIL- r2抗体目前正处于临床研究阶段，用于治疗不同的恶性肿瘤。TRAIL激活DR4和DR5，从而触发凋亡和非凋亡信号通路，但到目前为止，DR4或DR5在这些反应中可能发挥的不同作用尚未得到解决。在目前的工作中，我们分析了胰腺导管腺癌细胞对TRAIL和抗DR4 （mapatumumab）和抗DR5 （lexatumumab）的激动抗体的反应中细胞活力、DISC形成以及IL-8和NF-kappa B的激活。我们发现这三种试剂都能激活细胞死亡和促炎信号。死亡诱导信号复合体（DISC）分析显示，mapatumumab和lexatumumab诱导DR4或DR5同质复合体的形成，而TRAIL额外刺激了这两种受体异质复合体的形成。值得注意的是，使用DR4-和dr5特异性Fab片段阻断受体表明TRAIL主要通过DR4发挥其功能。有趣的是，Goe6983对PKC的抑制使DR5能够在TRAIL反应中触发凋亡信号，并强烈增强lexatumumab介导的细胞死亡。我们的研究结果表明，存在一种机制可以使DR5在TRAIL治疗中沉默，而不是在激动抗体治疗中沉默。
Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) and agonistic anti-DR4/TRAIL-R1 and anti-DR5/TRAIL-R2 antibodies are currently under clinical investigation for treatment of different malignancies. TRAIL activates DR4 and DR5 and thereby triggers apoptotic and non-apoptotic signaling pathways, but possible different roles of DR4 or DR5 in these responses has poorly been addressed so far. In the present work, we analyzed cell viability, DISC formation as well as IL-8 and NF-kappa B activation side by side in responses to TRAIL and agonistic antibodies against DR4 (mapatumumab) and against DR5 (lexatumumab) in pancreatic ductal adenocarcinoma cells. We found that all three reagents are able to activate cell death and pro-inflammatory signaling. Death-inducing signaling complex (DISC) analysis revealed that mapatumumab and lexatumumab induce formation of homocomplexes of either DR4 or DR5, whereas TRAIL additionally stimulated the formation of heterocomplexes of both receptors. Notably, blocking of receptors using DR4- and DR5-specific Fab fragments indicated that TRAIL exerted its function predominantly via DR4. Interestingly, inhibition of PKC by Goe6983 enabled DR5 to trigger apoptotic signaling in response to TRAIL and also strongly enhanced lexatumumab-mediated cell death. Our results suggest the existence of mechanisms that silence DR5 for TRAIL- but not for agonistic-antibody treatment.