Oncotarget

Research Papers:

A small molecule induces integrin β4 nuclear translocation and apoptosis selectively in cancer cells with high expression of integrin β4

ShuYan Liu, Di Ge, LiNa Chen, Jing Zhao, Le Su, ShangLi Zhang, JunYing Miao and BaoXiang Zhao _

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Oncotarget. 2016; 7:16282-16296. https://doi.org/10.18632/oncotarget.7646

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Abstract

ShuYan Liu1, Di Ge2,3, LiNa Chen1, Jing Zhao1, Le Su1, ShangLi Zhang1, JunYing Miao1,4, BaoXiang Zhao3

1Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University, Jinan 250100, China

2School of Biological Science and Technology, University of Jinan, Jinan 250022, China

3Institute of Organic Chemistry, School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China

4The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Shandong University, Jinan 250012, China

Correspondence to:

BaoXiang Zhao, e-mail: [email protected]

JunYing Miao, e-mail: [email protected]

Keywords: chemical small molecules, integrin β4 high expression cancer, ANXA7, ATF3, apoptosis

Received: September 14, 2015     Accepted: February 05, 2016     Published: February 23, 2016

ABSTRACT

Increased integrin β4 (ITGB4) level is accompanied by malignant progression of multiple carcinomas. However, selective therapeutic strategies against cancer cells expressing a high level of ITGB4 have not been reported. Here, for the first time, we report that a chiral small molecule, SEC, selectively promotes apoptosis in cancer cells expressing a high level of ITGB4 by inducing ITGB4 nuclear translocation. Nuclear ITGB4 can bind to the ATF3 promoter region and activate the expression of ATF3, then upregulate the downstream pro-apoptosis genes. Furthermore, SEC promoted the binding of annexin A7 (ANXA7) to ITGB4 and increased ANXA7 GTPase activity. Activated ANXA7 promoted ITGB4 nuclear translocation by triggering ITGB4 phosphorylation at Y1494. SEC also inhibited the growth of xenograft tumors in the avian embryo model. We identified a small molecule, SEC, with selective pro-apoptosis effects on cancer cells with high expression of ITGB4, both in vitro and in vivo, by triggering the binding of ITGB4 and ANXA7, ITGB4 nuclear trafficking, and pro-apoptosis gene expression.


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