Inhibition of Fibroblast Growth Factor 19 Reduces Tumor Growth by Modulating β-Catenin Signaling
- 1 July 2008
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 68 (13), 5086-5095
- https://doi.org/10.1158/0008-5472.can-07-2325
Abstract
Fibroblast growth factors (FGF) play important roles in development, angiogenesis, and cancer. FGF19 uniquely binds to FGF receptor 4 (FGFR4). Our previous study has shown that FGF19 transgenic tumors have an activated Wnt-pathway phenotype. Wnt signaling is implicated in initiating or promoting FGF signaling in various cell types and organs. In this study, we examined whether FGF19 or inhibition of FGF19 affects the β-catenin signaling pathway using human colon cancer cell lines (HCT116, Colo201). Our results show that FGF19 increases tyrosine phosphorylation of β-catenin and causes loss of β-catenin–E-cadherin binding. FGF19 increases p-GSK3β and active β-catenin levels and anti-FGF19 antibody (1A6) treatment abrogates this effect of FGF19. Anti-FGF19 antibody treatment increases S33/S37/T41 phosphorylation and ubiquitination of β-catenin. Ion-trap mass spectrometric analysis confirmed that 1A6 increases phosphorylation of β-catenin in the NH2 terminus. Using HCT116-paired β-catenin knockout cells, we show that FGF19 induces TCF/LEF reporter activity in parental (WT/Δ45) and in WT/− but not in mutant (−/Δ45) cells, and that inhibition of endogenous FGF19 reduces this reporter activity, indicating that wild-type β-catenin is accessible for modulation. FGFR4 knockdown using inducible short hairpin RNA significantly reduces the colony-forming ability in vitro and tumor growth in vivo. Although cleaved caspase-3 immunoreactivity remains unchanged, the number of ki67-positive nuclei is reduced in FGFR4 knockdown tumor xenograft tissues. Consistent with the reduced β-catenin activation, Taqman analyses show that FGF19/FGFR4 inhibition reduced β-catenin target gene (cyclin D1, CD44, c-jun, Cox-2, UPAR) expression. These findings highlight that FGF19/FGFR4 cross-talk with β-catenin and that pathway intervention reduces tumor growth. [Cancer Res 2008;68(13):5086–95]Keywords
Other Versions
This publication has 47 references indexed in Scilit:
- Liver-specific Activities of FGF19 Require Klotho betaPublished by Elsevier BV ,2007
- Targeting FGF19 inhibits tumor growth in colon cancer xenograft and FGF19 transgenic hepatocellular carcinoma modelsOncogene, 2007
- Functional FGFR4 Gly388Arg Polymorphism Predicts Prognosis in Lung Adenocarcinoma PatientsJournal of Clinical Oncology, 2005
- Erk Associates with and Primes GSK-3β for Its Inactivation Resulting in Upregulation of β-CateninMolecular Cell, 2005
- Targets of Fibroblast Growth Factor 1 (FGF-1) and FGF-2 Signaling Involved in the Invasive and Tumorigenic Behavior of Carcinoma CellsMolecular Biology of the Cell, 2004
- Involvement of the FGFR4 Arg388 allele in head and neck squamous cell carcinomaInternational Journal of Cancer, 2004
- Fibroblast growth factors in cancer: therapeutic possibilitiesEmerging Therapeutic Targets, 2002
- A Mouse Model of Hepatocellular CarcinomaThe American Journal of Pathology, 2002
- FGF-1 and FGF-2 regulate the expression of E-cadherin and catenins in pancreatic adenocarcinomaInternational Journal of Cancer, 2001
- FGF-19, A NOVEL FIBROBLAST GROWTH FACTOR WITH UNIQUE SPECIFICITY FOR FGFR4Cytokine, 1999