R-Etodolac decreases β-catenin levels along with survival and proliferation of hepatoma cells

Jaideep Behari, Gang Zeng, Wade Otruba, Michael D. Thompson, Peggy Muller, Amanda Micsenyi, Sandeep S. Sekhon, Lorenzo Leoni, Satdarshan P.S. Monga

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

Abstract

Background/Aims: Inhibition of hepatoma cells by cyclooxygenase (COX)-2-dependent and -independent mechanisms has been shown previously. Here, we examine the effect of Celecoxib, a COX-2-inhibitor and R-Etodolac, an enantiomer of the nonsteroidal anti-inflammatory drug Etodolac, which lacks COX-inhibitory activity, on the Wnt/β-catenin pathway and human hepatoma cells. Methods: Hep3B and HepG2 cell lines were treated with Celecoxib or R-Etodolac, and examined for viability, DNA synthesis, Wnt/β-catenin pathway components, and downstream target gene expression. Results: Celecoxib at high doses affected β-catenin protein by inducing its degradation via GSK3β and APC along with diminished tumor cell proliferation and survival. R-Etodolac at physiological doses caused decrease in total and activated β-catenin protein secondary to decrease in its gene expression and post-translationally through GSK3β activation. In addition, increased β-catenin-E-cadherin was also observed at the membrane. An associated inhibition of β-catenin-dependent Tcf reporter activity, decreased levels of downstream target gene products glutamine synthetase and cyclin-D1, and decreased proliferation and survival of hepatoma cells was evident. Conclusions: The antitumor effects of Celecoxib (at high concentrations) and R-Etodolac (at physiological doses) on HCC cells were accompanied by the down-regulation of β-catenin demonstrating a useful therapeutic strategy in hepatocellular cancer.

Original languageEnglish
Pages (from-to)849-857
Number of pages9
JournalJournal of Hepatology
Volume46
Issue number5
DOIs
StatePublished - May 2007

Keywords

  • Celecoxib
  • Cylooxygenase 2
  • Hepatocellular carcinoma
  • R-Etodolac
  • β-Catenin

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