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Molecular Cancer Therapeutics

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Research Article

Nuclear export of ubiquitinated proteins determines the sensitivity of colorectal cancer to proteasome inhibitor

Tingyu Wu, Wei Chen, Yongwang Zhong, Xiaodan Hou, Shengyun Fang, Chen-Ying Liu, Guanghui Wang, Tong Yu, Yu-Yang Huang, Xuesong Ouyang, Henry Q.X. Li, Long Cui and Yili Yang
Tingyu Wu
Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine
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Wei Chen
Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine
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Yongwang Zhong
Center for Biomedical Engineering and Technology, Department of Physiology, University of Maryland School of Medicine
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Xiaodan Hou
Suzhou Institute of Systems Medicine, Center for Systems Medicine Research, Chinese Academy of Medical Sciences
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Shengyun Fang
Center for Biomedical Engineering and Technology, Department of Physiology, University of Maryland School of Medicine
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Chen-Ying Liu
Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine
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Guanghui Wang
Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine
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Tong Yu
Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine
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Yu-Yang Huang
Crown Bioscience Inc.
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Xuesong Ouyang
Crown Bioscience Inc.
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Henry Q.X. Li
Crown Bioscience Inc.
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Long Cui
Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine
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Yili Yang
Suzhou Institute of Systems Medicine, Center for Systems Medicine Research, Chinese Academy of Medical Sciences
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  • For correspondence: yyl@ism.cams.cn
DOI: 10.1158/1535-7163.MCT-16-0553
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Abstract

Although proteasome inhibitors such as Bortezomib had significant therapeutic effects in multiple myeloma and mantel cell lymphoma, they exhibited minimal clinical activity as a mono-therapy for solid tumors, including colorectal cancer. We found in the present study that proteasome inhibition induced a remarkable nuclear exportation of ubiquitinated proteins. Inhibition of CRM1, the nuclear export carrier protein, hampered protein export and synergistically enhanced the cytotoxic action of Bortezomib on colon cancer cells containing wild type p53, which underwent G2/M cell cycle block and apoptosis. Further analysis indicated that tumor suppressor p53 was one of the proteins exported from nuclei upon proteasome inhibition, and in the presence of CRM1 inhibitor KPT330, nuclear p53 and expression of its target genes were increased markedly. Moreover, knockdown of p53 significantly reduced the synergistic cytotoxic action of Bortezomib and KPT330 on p53+/+ HCT116 cells. In mice, KPT330 markedly augmented the anti-tumor action of Bortezomib against HCT116 xenografts as well as patient-derived xenografts that harbored functional p53. These results indicate that nuclear p53 is a major mediator in the synergistic anti-tumor effect of Bortezomib and KPT330, and provides a rationale for the use of proteasome inhibitor together with nuclear export blocker in the treatment of colorectal cancer. It is conceivable that targeting nuclear exportation may serve as a novel strategy to overcome resistance and raise chemotherapeutic efficacy, especially for the drugs that activate the p53 system.

  • Received August 18, 2016.
  • Revision received November 2, 2016.
  • Accepted November 15, 2016.
  • Copyright ©2016, American Association for Cancer Research.
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Published OnlineFirst November 30, 2016
doi: 10.1158/1535-7163.MCT-16-0553

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Nuclear export of ubiquitinated proteins determines the sensitivity of colorectal cancer to proteasome inhibitor
Tingyu Wu, Wei Chen, Yongwang Zhong, Xiaodan Hou, Shengyun Fang, Chen-Ying Liu, Guanghui Wang, Tong Yu, Yu-Yang Huang, Xuesong Ouyang, Henry Q.X. Li, Long Cui and Yili Yang
Mol Cancer Ther November 30 2016 DOI: 10.1158/1535-7163.MCT-16-0553

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Nuclear export of ubiquitinated proteins determines the sensitivity of colorectal cancer to proteasome inhibitor
Tingyu Wu, Wei Chen, Yongwang Zhong, Xiaodan Hou, Shengyun Fang, Chen-Ying Liu, Guanghui Wang, Tong Yu, Yu-Yang Huang, Xuesong Ouyang, Henry Q.X. Li, Long Cui and Yili Yang
Mol Cancer Ther November 30 2016 DOI: 10.1158/1535-7163.MCT-16-0553
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Copyright 2016 by the American Association for Cancer Research.

Molecular Cancer Therapeutics
eISSN: 1538-8514
ISSN: 1535-7163

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