Abstract 1106: Fibroblast growth factor FGF19 signaling promotes prostate cancer progression

Abstract

Abstract Aberrant fibroblast growth factor (FGF) signaling can promote tumor development by directly driving cancer cell proliferation and survival, and by supporting tumor angiogenesis. Multiple FGFs have been found upregulated in prostate cancers, including FGF1, FGF2, FGF6, FGF8 and FGF17, all of which can activate FGF receptor 4 (FGFR4). FGFR4 is overexpressed in prostate cancer (PCa) and positively associated with aggressive PCa. FGF19 is a distinct member of FGF family in that it predominantly binds to FGFR4 with high affinity. In this present study we aimed to study the role of FGF19 in human PCa progression, and to determine whether the targeted suppression of FGF19/FGFR4 signaling has potential therapeutic benefits in PCa. Our results demonstrated that FGF19 is upregulated in human PCa compared to normal prostate tissues. FGF19 is expressed in an autocrine manner by all tested PCa cell lines. Exogenous FGF19 stimulates PCa cell proliferation, anchorage-independent growth, adhesion and invasion in vitro. The mRNAs of FGF19 co-receptors αKlotho and ßKlotho are expressed in 97.5% and 27.5% of PCa clinical samples, respectively; but αKlotho is expressed in only 57% normal prostate tissues, ßKlotho is barely detected in normal prostate tissues. Suppression of FGF19 by short hairpin RNA (shRNA) targeting FGF19 gene inhibits PCa cell proliferation, adhesion and invasiveness in vitro. Immunoprecipitation and western blot assays showed that FGF19 stimulates phosphorylation of FGFR4, FRS2α, Erk1/2 and p-38 MAPK, as well as MEK1/2 in both PC3 and DU145. Our data also revealed that FGF19 induced the serine/threonine protein kinase Akt phosphorylation in PCa cells. Lentiviral shRNA delivery was used for stable FGFR4 gene silencing in PC3 and LNCaP cells. The targeted knockdown of FGFR4 in PC3 and LNCaP cells resulted in significantly inhibited cell proliferation, invasion and remarkably reduced Akt phosphorylation. The upregulated expression of activated Caspase 8 and activated Caspase 3 in FGFR4 knockdown cells indicates that FGFR4 signaling inhibits PCa cell apoptosis. To determine if FGFR4 suppression impacts prostate tumor growth and metastasis in vivo we generated a PCa orthotopic xenograft model in which PC3-sh-FGFR4 or PC3-shV cells are injected directly into the prostates of nude mice in each group. The results revealed that the FGFR4 suppression in PCa cells significantly inhibited tumorigenicity in this model (P=0.01). The primary tumor weight was decreased by 63% in sh-FRGR4 tumors (p<0.05) and the proportion of mice with lymph node metastasis was decreased from 93.3% to 50% (p<0.01). The Ki67 immunohistochemistry showed a significant decrease of Ki67 positive cell percentage in PC3-sh-FGFR4 xenograft tumors (19.85%) compared to control group (35.93%, p<0.001). Our data indicated that FGF19/FGFR4 signaling may be a promising target in PCa therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1106. doi:10.1158/1538-7445.AM2011-1106