Antitumor Effect of Periplocin in TRAIL-Resistant gastric cancer cells via upregulation of death receptor through activating ERK1/2-EGR1 pathway
Antitumor Effect of Periplocin in TRAIL-Resistant gastric cancer cells via upregulation of death receptor through activating ERK1/2-EGR1 pathway
复制标题
Periplocin 通过激活 ERK1/2-EGR1 通路上调死亡受体对 TRAIL 耐药胃癌细胞的抗肿瘤作用
DOI：
10.1002/mc.22991
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发表时间：
2019-06-01
影响因子：
4.6
通讯作者：
Shan, Bao-En
中科院分区：
文献类型：
--
作者：
Zhao, Lian-Mei;Li, Lei;Shan, Bao-En
肿瘤坏死因子相关凋亡诱导配体（TRAIL）是肿瘤坏死因子家族的一员，可诱导多种癌细胞凋亡。然而，胃癌（GC）细胞通常对TRAIL不敏感。在前期的研究中，我们发现杠柳毒肽可以通过激活ERK 1/2-EGFR 1通路诱导胃癌细胞凋亡。在本研究中，我们已经表明，杠柳毒肽和TRAIL的组合在体外和体内对胃癌细胞活力的抑制作用比单独杠柳毒肽或TRAIL更大。杠柳毒肽通过在转录和蛋白水平上调DR 4和DR 5的表达，增强胃癌细胞对TRAIL的敏感性。ERK 1/2-EGR 1通路活性的增强导致杠柳毒肽处理后DR 4和DR 5的表达上调，进而导致Mcl-1和Bcl-2的表达降低，Bid和caspase-3/8的激活。总的来说，这些数据表明杠柳毒肽可能作为TRAIL的增敏剂，并可能成为治疗GC的潜在策略。
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor family, induces apoptosis in a variety of cancer cells. However, gastric cancer (GC) cells are insensitive to TRAIL usually. In the previous study, we showed that Periplocin could induce apoptosis in GC cells via the activation of ERK1/2-EGR1 pathway. In the present study, we have shown that the combination of Periplocin and TRAIL had a greater inhibitory effect on gastric cancer cell viability in vitro and in vivo than Periplocin or TRAIL alone. Through upregulating the expression of DR4 and DR5 at transcriptional and protein levels, Periplocin enhanced the sensitivity of gastric cancer cells to TRAIL. Furthermore, enhanced activity of ERK1/2-EGR1 pathway was responsible for upregulating of DR4 and DR5 uponPeriplocin treatment, subsequently reducing the expression of Mcl-1 and Bcl2 and activating Bid and caspase-3/8. Collectively, these data implied that Periplocin might act as a sensitizer of TRAIL and could be a potential strategy for the treatment of GC.