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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics

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Research Article

Notch inhibitor PF-03084014 inhibits hepatocellular carcinoma growth and metastasis via suppression of cancer stemness due to reduced activation of Notch1-Stat3

Chuan Xing Wu, Aimin Xu, Cathy C. Zhang, Peter Olson, Lin Chen, Terence K. Lee, Tan To Cheung, Chung Mau Lo and Xiao Qi Wang
Chuan Xing Wu
Department of Surgery, The University of Hong Kong
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Aimin Xu
Department of Medicine, The University of Hong Kong
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Cathy C. Zhang
Oncology Research Unit, Pfizer Global Research and Development
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Peter Olson
Oncology Research Unit, Pfizer Global Research and Development
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Lin Chen
Department of Surgery, The University of Hong Kong
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Terence K. Lee
Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University
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Tan To Cheung
Department of Surgery, The University of Hong Kong
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Chung Mau Lo
Department of Surgery, The University of Hong Kong
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Xiao Qi Wang
Department of Surgery, The University of Hong Kong
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  • For correspondence: HKUWang@gmail.com
DOI: 10.1158/1535-7163.MCT-17-0001
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Abstract

Aberrant activation of the Notch signaling pathway is implicated in many solid tumors, including hepatocellular carcinoma (HCC), indicating a potential use of Notch inhibitors for treatment. In this study, we investigated the antitumor and antimetastasis efficacy of the novel Notch inhibitor (γ-secretase inhibitor) PF-03084014 in HCC. HCC spherical cells (stem-like cancer cells), a sphere-derived orthotopic tumor model and one patient-derived xenograft (PDX) model were used in our experiment. We demonstrated that PF-03084014 inhibited the self-renewal and proliferation of cancer stem cells. PF-03084014 reduced the HCC sphere-derived orthotopic tumor and blocked the HCC tumor liver to lung metastasis. We further tested the PF-03084014 in PDX models and confirmed the inhibition tumor growth effect. In addition, a low dose of PF-03084014 induced HCC sphere differentiation, resulting in chemosensitization. Antitumor activity was associated with PF-03084014-induced suppression of Notch1 activity, decreased Stat3 activation and phosphorylation of the Akt signaling pathway, and reduced epithelial-mesenchymal transition. These are the key contributors to the maintenance of cancer stemness and the promotion of cancer metastasis. Moreover, the Notch-Stat3 association was implicated in the clinical HCC prognosis. Collectively, PF-03084014 revealed antitumor and antimetastatic effects in hepatocellular carcinoma, providing evidence for the potential use of GSIs as a therapeutic option for the treatment of HCC.

  • Received January 3, 2017.
  • Revision received March 29, 2017.
  • Accepted May 1, 2017.
  • Copyright ©2017, American Association for Cancer Research.
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Published OnlineFirst May 18, 2017
doi: 10.1158/1535-7163.MCT-17-0001

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Notch inhibitor PF-03084014 inhibits hepatocellular carcinoma growth and metastasis via suppression of cancer stemness due to reduced activation of Notch1-Stat3
Chuan Xing Wu, Aimin Xu, Cathy C. Zhang, Peter Olson, Lin Chen, Terence K. Lee, Tan To Cheung, Chung Mau Lo and Xiao Qi Wang
Mol Cancer Ther May 18 2017 DOI: 10.1158/1535-7163.MCT-17-0001

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Notch inhibitor PF-03084014 inhibits hepatocellular carcinoma growth and metastasis via suppression of cancer stemness due to reduced activation of Notch1-Stat3
Chuan Xing Wu, Aimin Xu, Cathy C. Zhang, Peter Olson, Lin Chen, Terence K. Lee, Tan To Cheung, Chung Mau Lo and Xiao Qi Wang
Mol Cancer Ther May 18 2017 DOI: 10.1158/1535-7163.MCT-17-0001
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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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