title: Destruxin B inhibits hepatocellular carcinoma cell growth through modulation of the Wnt/β-catenin signaling pathway and epithelial-mesenchymal transition.
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.
authors.affiliation: Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan; Department of Neurosurgery, University of Medicine and Pharmacy, Ho Chi Minh City, Viet Nam.
authors.forename: Thanh-Tuan
authors.initials: TT
authors.lastname: Huynh
authors.affiliation: Institute of Biochemical Sciences and Technology, Chaoyang University of Technology, Taichung, Taiwan.
authors.forename: Yerra Koteswara
authors.initials: YK
authors.lastname: Rao
authors.affiliation: Department of Pathology, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan.
authors.forename: Wei-Hwa
authors.initials: WH
authors.lastname: Lee
authors.affiliation: Departments of Surgery, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan.
authors.forename: Hsin-An
authors.initials: HA
authors.lastname: Chen
authors.affiliation: Department of Hepatitis, Cho Ray Hospital, Ho Chi Minh City, Viet Nam.
authors.forename: T Do-Quyen
authors.initials: TD
authors.lastname: Le
authors.affiliation: Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung, Taiwan.
authors.forename: David T W
authors.initials: DT
authors.lastname: Tzeng
authors.affiliation: Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan; Division of Thoracic Surgery, Department of Surgery, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan.
authors.forename: Liang-Shun
authors.initials: LS
authors.lastname: Wang
authors.affiliation: The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Alexander T H
authors.initials: AT
authors.lastname: Wu
authors.affiliation: Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yuh-Feng
authors.initials: YF
authors.lastname: Lin
authors.affiliation: Institute of Biochemical Sciences and Technology, Chaoyang University of Technology, Taichung, Taiwan. Electronic address: ymtzeng@cyut.edu.tw.
authors.forename: Yew-Min
authors.initials: YM
authors.lastname: Tzeng
authors.affiliation: Graduate 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.
authors.forename: Chi-Tai
authors.initials: CT
authors.lastname: Yeh
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D047630:Depsipeptides / Q000737:chemistry / Q000494:pharmacology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects* / Q000502:physiology; D022781:Hepatocytes / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D015394:Molecular Structure; D060449:Wnt Signaling Pathway / Q000187:drug effects* / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D047630:Depsipeptides; C040424:destruxin B
keywords: Destruxin B; EMT; HCC; Metastasis; Sorafenib combination; Wnt/β-catenin