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, Kin Wah Lee, Tan To Cheung, Chung Mau Lo, Xiao Qi Wang

Research output: Journal article publicationJournal articleAcademic researchpeer-review

32 Citations (Scopus)

Abstract

Aberrant activation of the Notch signaling pathway is implicated in many solid tumors, including hepatocellular carcinoma, indicating a potential use of Notch inhibitors for treatment. In this study, we investigated the antitumor and antimetastasis efficacy of the novel Notch inhibitor (g-secretase inhibitor) PF-03084014 in hepatocellular carcinoma. Hepatocellular carcinoma 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 hepatocellular carcinoma sphere-derived orthotopic tumor and blocked the hepatocellular carcinoma 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 hepatocellular carcinoma 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 hepatocellular carcinoma prognosis. Collectively, PF-03084014 revealed antitumor and antimetastatic effects in hepatocellular carcinoma, providing evidence for the potential use of gamma-secretase inhibitors as a therapeutic option for the treatment of hepatocellular carcinoma.
Original languageEnglish
Pages (from-to)1531-1543
Number of pages13
JournalMolecular Cancer Therapeutics
Volume16
Issue number8
DOIs
Publication statusPublished - 1 Aug 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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