title: Targeting the Wnt/β-catenin signaling pathway in liver cancer stem cells and hepatocellular carcinoma cell lines with FH535.
abstract: Activation of the Wnt/β-catenin pathway has been observed in at least 1/3 of hepatocellular carcinomas (HCC), and a significant number of these have mutations in the β-catenin gene. Therefore, effective inhibition of this pathway could provide a novel method to treat HCC. The purposed of this study was to determine whether FH535, which was previously shown to block the β-catenin pathway, could inhibit β-catenin activation of target genes and inhibit proliferation of Liver Cancer Stem Cells (LCSC) and HCC cell lines. Using β-catenin responsive reporter genes, our data indicates that FH535 can inhibit target gene activation by endogenous and exogenously expressed β-catenin, including the constitutively active form of β-catenin that contains a Serine37Alanine mutation. Our data also indicate that proliferation of LCSC and HCC lines is inhibited by FH535 in a dose-dependent manner, and that this correlates with a decrease in the percentage of cells in S phase. Finally, we also show that expression of two well-characterized targets of β-catenin, Cyclin D1 and Survivin, is reduced by FH535. Taken together, this data indicates that FH535 has potential therapeutic value in treatment of liver cancer. Importantly, these results suggest that this therapy may be effective at several levels by targeting both HCC and LCSC.
authors.affiliation: Department of Surgery, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Roberto
authors.initials: R
authors.lastname: Gedaly
authors.affiliation: Department of Surgery, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Roberto
authors.initials: R
authors.lastname: Galuppo
authors.affiliation: Department of Surgery, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Daily
authors.affiliation: Department of Surgery, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Malay
authors.initials: M
authors.lastname: Shah
authors.affiliation: Department of Surgery, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Erin
authors.initials: E
authors.lastname: Maynard
authors.affiliation: Department of Surgery, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Changguo
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Physiology, University of Kentucky, Lexington, Kentucky United States of America.
authors.forename: Xiping
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Physiology, University of Kentucky, Lexington, Kentucky United States of America.
authors.forename: Karyn A
authors.initials: KA
authors.lastname: Esser
authors.affiliation: Department of Microbiology, Immunology & Molecular Genetics, University of Kentucky, Lexington, Kentucky, United States of America; Markey Cancer Center, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Donald A
authors.initials: DA
authors.lastname: Cohen
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: B Mark
authors.initials: BM
authors.lastname: Evers
authors.affiliation: Department of Microbiology, Immunology & Molecular Genetics, University of Kentucky, Lexington, Kentucky, United States of America; Markey Cancer Center, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Jieyun
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Department of Microbiology, Immunology & Molecular Genetics, University of Kentucky, Lexington, Kentucky, United States of America; Markey Cancer Center, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Brett T
authors.initials: BT
authors.lastname: Spear
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000473:pathology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology*; D058990:Molecular Targeted Therapy; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology*; D000077022:Survivin; D015533:Transcriptional Activation / Q000187:drug effects; D060449:Wnt Signaling Pathway / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; C530104:CCND1 protein, human; C575430:FH535; D051034:Inhibitor of Apoptosis Proteins; D013449:Sulfonamides; D000077022:Survivin; D019938:Cyclin D1