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, Hiroki Yokota

Research output: Contribution to journalArticle

1 Scopus citations

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 RNAseq 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.

Original languageEnglish (US)
Pages (from-to)9364-9378
Number of pages15
JournalOncotarget
Volume9
Issue number10
DOIs
StatePublished - Jan 1 2018

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Keywords

  • Bone resorption
  • Breast cancer
  • Checkpoint kinase
  • EIF2α

ASJC Scopus subject areas

  • Oncology

Cite this

Liu, S., Liu, Y., Minami, K., Chen, A., Wan, Q., Yin, Y., Gan, L., Xu, A., Matsuura, N., Koizumi, M., Liu, Y., Na, S., Li, J., Nakshatri, H., Li, B. Y., & Yokota, H. (2018). Inhibiting checkpoint kinase 1 protects bone from bone resorption by mammary tumor in a mouse model. Oncotarget, 9(10), 9364-9378. https://doi.org/10.18632/oncotarget.24286