The UPR inducer DPP23 inhibits the metastatic potential of MDA-MB-231 human breast cancer cells by targeting the Akt-IKK-NF-κB-MMP-9 axis.
The UPR inducer DPP23 inhibits the metastatic potential of MDA-MB-231 human breast cancer cells by targeting the Akt-IKK-NF-κB-MMP-9 axis.
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DOI：
10.1038/srep34134
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发表时间：
2016-09-23
影响因子：
4.6
通讯作者：
Lee YH
中科院分区：
文献类型：
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作者：
Shin SY;Kim CG;Jung YJ;Lim Y;Lee YH
(E)-3-（3,5-二甲氧基苯基）-1-（2-甲氧基苯基）prop-2-en-1-one （DPP23）是一种合成多酚衍生物，通过未折叠的蛋白反应途径选择性诱导癌细胞凋亡。在本研究中，我们评估了DPP23对肿瘤侵袭和转移的影响。在这里，我们发现DPP23抑制肿瘤坏死因子α (TNFα)诱导的运动、f -肌动蛋白的形成和MDA-MB-231细胞的侵袭能力。DPP23在转录水平上抑制NF-κ b依赖性MMP-9的表达。Akt参与NF-κB上游调控因子IKK的激活。DPP23抑制IKK和Akt，敲低Akt2显著抑制tnf α诱导的IKK磷酸化。通过硅分子对接分析，我们发现DPP23与Akt2的催化结构域结合。这些结果表明，DPP23通过抑制Akt-IKK-NF -κB轴介导的MMP-9基因表达，阻止tnf α-诱导的高转移性MDA-MB-231乳腺癌细胞的侵袭。此外，DPP23在使用4T1小鼠乳腺癌细胞的同基因脾内移植模型中减轻了实验性肝转移。综上所述，这些结果表明DPP23可以作为预防早期乳腺癌侵袭和转移的潜在平台或作为化疗/放疗的辅助手段。
(E)-3-(3,5-dimethoxyphenyl)-1-(2-methoxyphenyl)prop-2-en-1-one (DPP23) is a synthetic polyphenol derivative that selectively induces apoptosis in cancer cells through the unfolded protein response pathway. In the present study, we evaluated the effect of DPP23 on tumour invasion and metastasis. Here, we show that DPP23 inhibited tumour necrosis factor alpha (TNFα)-induced motility, F-actin formation, and the invasive capability of MDA-MB-231 cells. DPP23 inhibited NF-κB-dependent MMP-9 expression at the transcriptional level. Akt is involved in the activation of IKK, an upstream regulator of NF-κB. DPP23 inhibited IKK and Akt, and knockdown of Akt2 significantly inhibited TNFα-induced IKK phosphorylation. We found that DPP23 bound to the catalytic domain of Akt2, as revealed by an in silico molecular docking analysis. These results suggest that DPP23 prevents TNFα-induced invasion of highly metastatic MDA-MB-231 breast cancer cells by inhibiting Akt–IKK–NF-κB axis-mediated MMP-9 gene expression. In addition, DPP23 attenuated experimental liver metastasis in a syngenic intrasplenic transplantation model using 4T1 mouse mammary carcinoma cells. Collectively, these results suggest that DPP23 could be used as a potential platform for the prevention of invasion and metastasis of early-stage breast cancer or as an adjuvant for chemo/radiotherapy.
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影响因子：
11.2
作者：
Dillon RL;Marcotte R;Hennessy BT;Woodgett JR;Mills GB;Muller WJ
通讯作者：
Muller WJ
影响因子：
4.3
作者：
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Choi, Yung Hyun
影响因子：
3.1
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通讯作者：
Harlan, JM
影响因子：
9.7
作者：
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通讯作者：
Shin, Soon Young
影响因子：
64.8
作者：
通讯作者：
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