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Toxicol In Vitro. 2014 Jun;28(4):552-61. doi: 10.1016/j.tiv.2014.01.002. Epub 2014 Jan 13.

Destruxin B inhibits hepatocellular carcinoma cell growth through modulation of the Wnt/β-catenin signaling pathway and epithelial-mesenchymal transition.

Author information

  • 1Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan; Department of Neurosurgery, University of Medicine and Pharmacy, Ho Chi Minh City, Viet Nam.
  • 2Institute of Biochemical Sciences and Technology, Chaoyang University of Technology, Taichung, Taiwan.
  • 3Department of Pathology, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan.
  • 4Departments of Surgery, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan.
  • 5Department of Hepatitis, Cho Ray Hospital, Ho Chi Minh City, Viet Nam.
  • 6Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung, Taiwan.
  • 7Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan; Division of Thoracic Surgery, Department of Surgery, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan.
  • 8The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
  • 9Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan.
  • 10Institute of Biochemical Sciences and Technology, Chaoyang University of Technology, Taichung, Taiwan. Electronic address: ymtzeng@cyut.edu.tw.
  • 11Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan; Departments of Surgery, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan; Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan. Electronic address: ctyeh@tmu.edu.tw.

Abstract

The aberrant activation of Wnt/β-catenin signaling plays an important role in the carcinogenesis and progression of hepatocellular carcinoma (HCC). Therefore, the Wnt/β-catenin signaling molecules are attractive candidates for the development of targeted therapies for this disease. The present study showed that destruxin B (DB) inhibits the proliferation and induces the apoptosis of HCC cells by decreasing the protein expression of anti-apoptotic Bcl-2 and Bcl-xL and increasing the expression of the proapoptotic protein Bax. More importantly, DB also attenuates Wnt-signaling in HCC cells by downregulating β-catenin, Tcf4, and β-catenin/Tcf4 transcriptional activity, which results in the decreased expression of β-catenin target genes, such as cyclin D1, c-myc, and survivin. Furthermore, DB affects the migratory and invasive abilities of Sk-Hep1 cells through the suppression of markers of the epithelial-mesenchymal transition (EMT). A synergistic anti-proliferative and migratory effect was achieved using the combination of DB and sorafenib in Sk-Hep1 cells. In conclusion, DB acts as a novel Wnt/β-catenin inhibitor and reduces the aggressiveness and invasive potential of HCC by altering the cells' EMT status and mobility. DB in combination with sorafenib may be considered for future clinical use for the management of metastatic HCC.

KEYWORDS:

Destruxin B; EMT; HCC; Metastasis; Sorafenib combination; Wnt/β-catenin

PMID:
24434019
DOI:
10.1016/j.tiv.2014.01.002
[PubMed - indexed for MEDLINE]
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