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三氧化二砷以Pin1为靶点并与维甲酸合作抑制促癌通路和肿

 2018/11/8 9:19:22 《最新论文》 作者:Nature Communications 我有话说(0人评论) 字体大小:+

论文标题:Arsenic targets Pin1 and cooperates with retinoic acid to inhibit cancer-driving pathways and tumor-initiating cells

期刊:Nature Communications

作者:Shingo Kozono, Yu-Min Lin, Hyuk-Soo Seo, Benika Pinch, Xiaolan Lian, Chenxi Qiu, Megan K. Herbert, Chun-Hau Chen, Li Tan, Ziang Jeff Gao, Walter Massefski, Zainab M. Doctor, Brian P. Jackson, Yuanzhong Chen, Sirano Dhe-Paganon, Kun Ping Lu, Xiao Zhen Zhou

发表时间:2018/08/09

数字识别码:10.1038/s41467-018-05402-2

原文链接:http://t.cn/EwQbKUU

三氧化二砷(Arsenic trioxide, ATO)和全反式维甲酸(all-trans retinoic acid, ATRA)的组合使用能安全地治愈致命性的急性早幼粒细胞白血病,但它们的作用机制和疗效尚不完全清楚。ATRA通过针对异构酶Pin1来抑制白血病、乳腺癌和肝癌,这种异构酶Pin1是促癌信号网络的主要调节因子。

近日,《自然-通讯》发表的文章Arsenic targets Pin1 and cooperates with retinoic acid to inhibit cancer-driving pathways and tumor-initiating cells进一步描述了以Pin1为核心的调控机制。

来自哈佛大学医学院的Kun Ping Lu、Xiao Zhen Zhou及其同事发现,ATO靶向Pin1,并与维甲酸共同作用来发挥有效的抗癌活性。ATO抑制并降解Pin1,并通过非共价地结合Pin1的活性位点来抑制其致癌功能。ATRA则通过上调水通道蛋白-9来增加细胞对ATO的摄取。通过全面的蛋白质和microRNA分析证实,在包括人源原位移植瘤在内的细胞和动物模型中,临床安全剂量下的ATO和ATRA能共同作用以消除Pin1,从而阻断多条促癌通路并抑制三阴性乳腺癌细胞和肿瘤起始细胞的生长,即对Pin1进行了消除。

因此,ATO和ATRA对Pin1的协同作用为人类对抗乳腺癌和其他癌症提供了新思路。

图1:ATO和ATRA在靶向Pin1中的协同作用模型。这种靶向作用阻断了多条促癌通路并消除癌了癌症干细胞,而这两个恰恰是癌症耐药性的主要原因。

摘要:Arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) combination safely cures fatal acute promyelocytic leukemia, but their mechanisms of action and efficacy are not fully understood. ATRA inhibits leukemia, breast, and liver cancer by targeting isomerase Pin1, a master regulator of oncogenic signaling networks. Here we show that ATO targets Pin1 and cooperates with ATRA to exert potent anticancer activity. ATO inhibits and degrades Pin1, and suppresses its oncogenic function by noncovalent binding to Pin1’s active site. ATRA increases cellular ATO uptake through upregulating aquaporin-9. ATO and ATRA, at clinically safe doses, cooperatively ablate Pin1 to block numerous cancer-driving pathways and inhibit the growth of triple-negative breast cancer cells and tumor-initiating cells in cell and animal models including patient-derived orthotopic xenografts, like Pin1 knockout, which is substantiated by comprehensive protein and microRNA analyses. Thus, synergistic targeting of Pin1 by ATO and ATRA offers an attractive approach to combating breast and other cancers.

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期刊介绍:Nature Communications (https://www.nature.com/ncomms/) is an open access journal that publishes high-quality research from all areas of the natural sciences. Papers published by the journal represent important advances of significance to specialists within each field.

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来源:Nature Communications