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Apo2L/TRAIL与腺病毒-p53在骨髓瘤细胞系凋亡诱导中的相加作用。

Additive effect of Apo2L/TRAIL and Adeno-p53 in the induction of apoptosis in myeloma cell lines.

作者信息

Liu Q, El-Deiry W S, Gazitt Y

机构信息

University of Texas Health Science Center, San Antonio, Tex., USA.

出版信息

Exp Hematol. 2001 Aug;29(8):962-70. doi: 10.1016/s0301-472x(01)00677-4.

DOI:10.1016/s0301-472x(01)00677-4
PMID:11495702
Abstract

OBJECTIVE

We have previously shown that Adenovirus-p53 (Ad-p53) is a potent inducer of apoptosis in myeloma cells expressing nonfunctional p53 and low levels of bcl-2 and that Apo2L/TRAIL is a potent inducer of apoptosis, independent of bcl-2. A study was designed to test the synergy between Ad-p53 and Apo2L/TRAIL in the induction of apoptosis in relation to the expression of DR4/DR5 and DcR1, in cells undergoing Ad-p53-induced apoptosis.

METHODS

Replication deficient Ad-p53 and human recombinant Apo2L/TRAIL were used. Myeloma cells with mutated/w.t. p53 and varying expression of bcl-2 were used to test the effect of Ad-p53, Apo2L/TRAIL, or both, on apoptosis, measured by annexin V.

RESULTS

Treatment with Ad-p53 resulted in a dose-dependent apoptosis concomitant with a dose-dependent increase in the expression of DR4/DR5 and a decrease in the expression of DcR1, in Ad-p53-sensitive cell lines. In these cells, addition of Apo2L/TRAIL to cells treated with Ad-p53 resulted in a dose-dependent increase in apoptosis. Myeloma cells resistant to Ad-p53 had high levels of DR4/DR5 and high levels of DcR1 and treatment with Ad-p53 did not reduce the expression of DcR1. Also, addition of Apo2L/TRAIL to Ad-p53 did not affect the level of apoptosis beyond the level of apoptosis observed with Apo2L/TRAIL alone.

CONCLUSIONS

  1. Cotreatment with Ad-p53 and Apo2L/TRAIL resulted in additive apoptosis in myeloma cells expressing nonfunctional p53 and low levels of bcl-2. 2) Resistance to Ad-p53 or to the combination of Ad-p53 and Apo2L/TRAIL was not due to the lack of adenovirus receptor (CAR) or low expression of DR4/DR5 but rather due to the relatively high expression of DcR1 receptor.
摘要

目的

我们之前已经表明，腺病毒 - p53（Ad - p53）是表达无功能p53和低水平bcl - 2的骨髓瘤细胞中凋亡的有效诱导剂，并且Apo2L/TRAIL是一种独立于bcl - 2的凋亡有效诱导剂。本研究旨在测试Ad - p53与Apo2L/TRAIL在诱导凋亡方面的协同作用，该协同作用与正在经历Ad - p53诱导凋亡的细胞中DR4/DR5和DcR1的表达相关。

方法

使用复制缺陷型Ad - p53和人重组Apo2L/TRAIL。具有突变型/野生型p53以及不同bcl - 2表达水平的骨髓瘤细胞用于测试Ad - p53、Apo2L/TRAIL或两者对凋亡的影响，通过膜联蛋白V进行检测。

结果

在Ad - p53敏感细胞系中，用Ad - p53处理导致剂量依赖性凋亡，同时DR4/DR5表达呈剂量依赖性增加，DcR1表达降低。在这些细胞中，向用Ad - p53处理的细胞中添加Apo2L/TRAIL导致凋亡呈剂量依赖性增加。对Ad - p53耐药的骨髓瘤细胞具有高水平的DR4/DR5和高水平的DcR1，用Ad - p53处理并未降低DcR1的表达。此外，向Ad - p53中添加Apo2L/TRAIL对凋亡水平的影响不超过单独使用Apo2L/TRAIL时观察到的凋亡水平。

结论

1）Ad - p53与Apo2L/TRAIL联合处理在表达无功能p53和低水平bcl - 2的骨髓瘤细胞中导致相加性凋亡。2）对Ad - p53或Ad - p53与Apo2L/TRAIL组合的耐药性不是由于缺乏腺病毒受体（CAR）或DR4/DR5低表达，而是由于DcR1受体相对高表达。

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