Oncotarget

Research Papers:

APIO-EE-9 is a novel Aurora A and B antagonist that suppresses esophageal cancer growth in a PDX mouse model

Guoguo Jin, Ke Yao, Zhiping Guo, Zhenjiang Zhao, Kangdong Liu, Fangfang Liu, Hanyong Chen, Dhilli Rao Gorja, Kanamata Reddy, Ann M. Bode, Ziming Dong and Zigang Dong _

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Oncotarget. 2017; 8:53387-53404. https://doi.org/10.18632/oncotarget.18508

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Abstract

Guoguo Jin1,2,3*, Ke Yao1,3,*, Zhiping Guo1,4,*, Zhenjiang Zhao1,4,*, Kangdong Liu1,2,3, Fangfang Liu3, Hanyong Chen1, Dhilli Rao Gorja3, Kanamata Reddy1, Ann M. Bode1, Ziming Dong2 and Zigang Dong1,3

1The Hormel Institute, University of Minnesota, Austin, Minnesota, USA

2Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, P.R. China

3China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, P.R. China

4The Henan Luoyang Orthopedic Hospital, Zhengzhou, Henan, P.R. China

*These authors have contributed equally to this work

Correspondence to:

Zigang Dong, email: zgdong@hi.umn.edu

Ziming Dong, email: dongzm@zzu.edu.cn

Keywords: targeted therapy, aurora kinases, mitosis, esophageal cancer

Received: November 17, 2016     Accepted: May 10, 2017     Published: June 16, 2017

ABSTRACT

Esophageal cancer (EC) is one of the most aggressive malignancies of the upper aerodigestive tract. Over the past three decades, with advances in surgical techniques and treatment, the prognosis of esophageal cancer has only slowly improved. Thus identifying novel molecular targets and developing therapeutic agents are critical. Aurora kinases play a crucial role in mitosis and selective inhibitors might provide an effective therapeutic treatment for cancer. However, the role of Aurora kinases in EC is still inadequately studied. Here, we identified a novel compound, referred to as APIO-EE-9, which inhibits growth and colony formation and induces apoptosis of esophageal cancer cells. Using computer modeling, we found that APIO-EE-9 interacted with both Aurora A and B in the ATP-binding pocket. APIO-EE-9 inhibited both Aurora A and B kinase activities in a dose-dependent manner. Treatment with APIO-EE-9 substantially reduced the downstream Aurora kinase phosphorylation of histone H3 (Ser10), resulting in formation of multiple nuclei and centrosomes. Additionally, esophageal cancer cells expressing shAurora A or shAurora B kinase exhibited a dramatic reduction in proliferation and colony formation. Injection of these cells as xenografts in mice reduced tumor formation compared to wildtype cells. Importantly, APIO-EE-9 significantly decreased the size of esophageal patient-derived xenograft (PDX) tumors implanted in SCID mice. These results demonstrated that APIO-EE-9 is a specific Aurora kinase inhibitor that could be developed as a therapeutic agent against esophageal cancer.


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