Notch Inhibitor PF-03084014 Inhibits Hepatocellular Carcinoma Growth and Metastasis via Suppression of Cancer Stemness due to Reduced Activation of Notch1-Stat3.

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 (γ-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. Mol Cancer Ther; 16(8); 1531-43. ©2017 AACR.

• Authors: Chuan Xing Wu, Aimin Xu, Cathy C Zhang, Peter Olson, Lin Chen, Terence K Lee, Tan To Cheung, Chung Mau Lo, Xiao Qi Wang
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 16 Issue 8 Pg. 1531-1543 (08 2017) ISSN: 1538-8514 [Electronic] United States
• PMID: 28522590 (Publication Type: Journal Article)
• Copyright: ©2017 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Receptor, Notch1
• STAT3 Transcription Factor
• Tetrahydronaphthalenes
• Valine
• nirogacestat

Topics

• Antineoplastic Agents (pharmacology, therapeutic use)
• Carcinogenesis (drug effects, metabolism, pathology)
• Carcinoma, Hepatocellular (drug therapy, pathology)
• Cell Differentiation (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Self Renewal (drug effects)
• Humans
• Liver Neoplasms (drug therapy, pathology)
• Neoplasm Metastasis
• Neoplastic Stem Cells (drug effects, metabolism, pathology)
• Receptor, Notch1 (antagonists & inhibitors, metabolism)
• STAT3 Transcription Factor (metabolism)
• Spheroids, Cellular (drug effects, metabolism, pathology)
• Tetrahydronaphthalenes (pharmacology, therapeutic use)
• Valine (analogs & derivatives, pharmacology, therapeutic use)