A BAP31 intrabody induces gastric cancer cell death by inhibiting p27kip1 proteasome degradation
A BAP31 intrabody induces gastric cancer cell death by inhibiting p27kip1 proteasome degradation
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BAP31 体内通过抑制 p27(kip1) 蛋白酶体降解来诱导胃癌细胞死亡。
DOI：
10.1002/ijc.31930
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发表时间：
2019-04-15
影响因子：
6.4
通讯作者：
Wang, Bing
中科院分区：
文献类型：
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作者：
Chen, Jing;Guo, Haotian;Wang, Bing
B细胞受体相关蛋白31（BAP 31）是一种广泛表达的内质网（ER）膜蛋白，在胃腺癌中过度表达。我们首先研究了BAP 31与84种肿瘤相关抗原的关系，发现BAP 31可以特异性地与细胞周期蛋白激酶抑制剂p27（kip 1）的蛋白酶体降解相互作用并调节其降解，而kip 1是人类癌症中最常见的失调肿瘤抑制蛋白之一。因此，我们从人VH单结构域抗体文库中筛选针对BAP 31的抗体，并在细胞内表达抗体。发现其中一种胞内抗体（VH-D1）特异性抑制p27（kip1）蛋白酶体降解，可能是通过阻断BAP 31与p27（kip1）的结合。VH-D1显示出治疗效果，因为它能够减少裸鼠中人胃癌（GC）细胞异种移植物的生长。这种效应是由于抑制增殖和随后激活半胱天冬酶依赖性凋亡。因此，BAP 31是通过基于胞内抗体的方法抑制GC的潜在靶标。
B-cell receptor-associated protein 31 (BAP31) is a ubiquitously expressed endoplasmic reticulum (ER) membrane protein that has been found to be overexpressed in gastric intestinal-type adenocarcinoma. We first studied the relationship of BAP31 with 84 kinds of tumor-associated antigens and found that BAP31 can specifically interact with and regulate the proteasome degradation of the cyclin kinase inhibitor p27(kip1), which is one of the most frequently dysregulated tumor suppressor proteins in human cancers. Therefore, we screened antibodies against BAP31 from a human VH single-domain antibody library and expressed the antibodies intracellularly. It was found that one of the intrabodies (VH-D1) specifically inhibited p27(kip1) proteasome degradation, possibly by blocking the combination of BAP31 with p27(kip1). VH-D1 displayed therapeutic effects, as it was able to reduce the growth of human gastric cancer (GC) cell xenografts in nude mice. This effect was due to inhibition of the proliferation and subsequent activation of caspase-dependent apoptosis. Thus, BAP31 is a potential target for the suppression of GC via an intrabody-based approach.