Oncotarget

Research Papers:

Inhibiting checkpoint kinase 1 protects bone from bone resorption by mammary tumor in a mouse model

Shengzhi Liu, Yang Liu, Kazumasa Minami, Andy Chen, Qiaoqiao Wan, Yukun Yin, Liangying Gan, Aihua Xu, Nariaki Matsuura, Masahiko Koizumi, Yunlong Liu, Sungsoo Na, Jiliang Li, Harikrishna Nakshatri, Bai-Yan Li and Hiroki Yokota _

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Oncotarget. 2018; 9:9364-9378. https://doi.org/10.18632/oncotarget.24286

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Abstract

Shengzhi Liu1,2, Yang Liu1,2, Kazumasa Minami2,3, Andy Chen2, Qiaoqiao Wan2, Yukun Yin4, Liangying Gan4, Aihua Xu4, Nariaki Matsuura5, Masahiko Koizumi3, Yunlong Liu6, Sungsoo Na2, Jiliang Li4, Harikrishna Nakshatri7, Bai-Yan Li1 and Hiroki Yokota2

1Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin 150081, China

2Department of Biomedical Engineering, Indiana University at Purdue University, Indianapolis, IN 46202, USA

3Department of Medical Physics and Engineering, Osaka University Graduate School of Medicine Suita, Osaka 565-0871, Japan

4Department of Biology, Indiana University at Purdue University, Indianapolis, IN 46202, USA

5Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 537-8511, Japan

6Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA

7Department of Surgery, Simon Cancer Research Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA

Correspondence to:

Hiroki Yokota, email: [email protected]

Bai-Yan Li, email: [email protected]

Keywords: breast cancer; bone resorption; checkpoint kinase; eIF2α

Received: October 27, 2017     Accepted: January 13, 2018     Published: January 19, 2018

ABSTRACT

DNA damage response plays a critical role in tumor growth, but little is known about its potential role in bone metabolism. We employed selective inhibitors of Chk1 and examined their effects on the proliferation and migration of mammary tumor cells as well as the development of osteoblasts and osteoclasts. Further, using a mouse model of bone metastasis we evaluated the effects of Chk1 inhibitors on bone quality. Chk1 inhibitors blocked the proliferation, survival, and migration of tumor cells in vitro and suppressed the development of bone-resorbing osteoclasts by downregulating NFATc1. In the mouse model, Chk1 inhibitor reduced osteolytic lesions and prevented mechanical weakening of the femur and tibia. Analysis of RNA-seq expression data indicated that the observed effects were mediated through the regulation of eukaryotic translation initiation factor 2 alpha, stress to the endoplasmic reticulum, S100 proteins, and bone remodeling-linked genes. Our findings suggest that targeting Chk1 signaling without adding DNA damaging agents may protect bone from degradation while suppressing tumor growth and migration.


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