Targeting the Wnt/β-catenin signaling pathway in liver cancer stem cells and hepatocellular carcinoma cell lines with FH535

Roberto Gedaly, Roberto Galuppo, Michael F. Daily, Malay Shah, Erin Maynard, Changguo Chen, Xiping Zhang, Karyn A. Esser, Donald A. Cohen, B. Mark Evers, Jieyun Jiang, Brett T. Spear

Research output: Contribution to journalArticle

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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 b-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.

Original languageEnglish (US)
Article numbere99272
JournalPLoS One
Volume9
Issue number6
DOIs
StatePublished - Jun 18 2014
Externally publishedYes

Fingerprint

Catenins
Wnt Signaling Pathway
Neoplastic Stem Cells
liver neoplasms
hepatoma
Liver Neoplasms
Stem cells
Liver
stem cells
Hepatocellular Carcinoma
Cells
cell lines
Cell Line
Genes
Chemical activation
mutation
therapeutics
gene activation
Transcriptional Activation
cyclins

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Targeting the Wnt/β-catenin signaling pathway in liver cancer stem cells and hepatocellular carcinoma cell lines with FH535. / Gedaly, Roberto; Galuppo, Roberto; Daily, Michael F.; Shah, Malay; Maynard, Erin; Chen, Changguo; Zhang, Xiping; Esser, Karyn A.; Cohen, Donald A.; Evers, B. Mark; Jiang, Jieyun; Spear, Brett T.

In: PLoS One, Vol. 9, No. 6, e99272, 18.06.2014.

Research output: Contribution to journalArticle

Gedaly, R, Galuppo, R, Daily, MF, Shah, M, Maynard, E, Chen, C, Zhang, X, Esser, KA, Cohen, DA, Evers, BM, Jiang, J & Spear, BT 2014, 'Targeting the Wnt/β-catenin signaling pathway in liver cancer stem cells and hepatocellular carcinoma cell lines with FH535', PLoS One, vol. 9, no. 6, e99272. https://doi.org/10.1371/journal.pone.0099272
Gedaly, Roberto ; Galuppo, Roberto ; Daily, Michael F. ; Shah, Malay ; Maynard, Erin ; Chen, Changguo ; Zhang, Xiping ; Esser, Karyn A. ; Cohen, Donald A. ; Evers, B. Mark ; Jiang, Jieyun ; Spear, Brett T. / Targeting the Wnt/β-catenin signaling pathway in liver cancer stem cells and hepatocellular carcinoma cell lines with FH535. In: PLoS One. 2014 ; Vol. 9, No. 6.
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