[Background] The WNT/β-catenin signaling pathway is a major oncogenic pathway of human hepatocellular carcinoma (HCC). More than 50% of HCCs have aberrant activation of WNT/β-catenin signaling, which are caused by genetic alterations, ligand activation, or cross-activation by other signaling pathways. We hypothesized that activating mutation of CTNNB1, the coding gene of β-catenin, may confer sensitivity to WNT/β-catenin inhibitors in HCC cells.
[Materials and Methods] SNU398 is a human HCC cell line harboring a missense somatic mutation in exon 3 of CTNNB1 gene, resulting in S37C mutation. Huh7, HepG2, PLC5, and Hep3B are HCC cells containing no somatic mutations in exon 3 of CTNNB1 gene. HCC cells were treated with various types of WNT/β-catenin pathway inhibitors, including ICG-001 which down-regulates β-catenin/TCF transcriptional activity by interfering the binding of β-catenin with its transcriptional activation complex, XAV939 which targets tankyrases and facilitates degradation of β-catenin, and LGK974 which inhibits Porcupine, an acyltransferase responsible for palmitoylation and secretion of Wnt ligands, and evaluated for in vitro viability by MTT.
[Results] ICG-001 as a single agent showed significantly greater anti-proliferation effect in SNU398 than other HCC cells. The 50%-inhibitory concentrations (IC50s) of ICG-001 were 5 μM and >10 μM for SNU398 and other HCC cells, respectively. ICG-001 also induced a more potent suppression of colony- formation, and a more significant increase of subG1 fraction detected by flow cytometry in SNU398 cell than other HCC cells. XAV939 up to 20 μM induced only modest anti-proliferative effect in all HCC cells. However, SNU398 remained the one showing the greatest sensitivity to the growth suppression induced by XAV939. The anti-proliferative effect of LGK974 was modest and showed no significant difference among different HCC cells.
[Conclusion] The activating mutation of β-catenin may confer sensitivity to certain WNT/β-catenin pathway inhibitors, such as ICG-001, in HCC cells. (This study was supported by grants NRPB-100CAP1020-2).
Citation Format: Hsiao-Hui Lin, Wen-Chi Feng, LI-Chun Lu, Ta-Wen Hsu, Ann-Lii Cheng, Chih-Hung Hsu. Increased sensitivity to Wnt/beta-catenin inhibitors in hepatocellular carcinoma cells harboring activating mutation of beta-catenin. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2625. doi:10.1158/1538-7445.AM2014-2625