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Inhibition of Fibroblast Growth Factor 19 Reduces Tumor Growth by Modulating β-Catenin Signaling

Departments of ¹ Pathology, ² Molecular Oncology, and ³ Protein Chemistry, Genentech Incorporated, South San Francisco, California

Requests for reprints: Rama Pai, Genentech, Inc., MS 72B, South San Francisco, CA 94080. Phone: 650-467-3688; Fax: 650-225-8989; E-mail: rpai{at}gene.com.

Key Words: FGF19 • FGFR4 • β-catenin • colon cancer • shRNA

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/45) and in WT/– but not in mutant (–/45) 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]