Abstract
Abstract Induction of cell proliferation is closely related with the cellular signaling pathway activation by stimulation of diverse growth factors such as epidermal growth factor (EGF) and fibroblast growth factor. The stimulation of growth factors induces activation of extracellular signal-regulated kinases (ERKs)/p90 ribosomal S6 kinases (p90RSK), resulting in induction of cell proliferation and cell transformation. Although fibroblast growth factor (FGF) is a well-known growth factor and acts as a ligand of FGF receptor (FGFR), a receptor tyrosine kinase, in cytoplasmic membrane, the tumor promoter potential has not been clearly understood. Here, we provided the evidences that FGF acted as a tumor promoter. We found that FGF-induced cell proliferation and anchorage-independent cell transformation were correlated with the induction of G1/S cell cycle transition. Importantly, we found that kaempferol targeted and inhibited FGFR phosphorylation by in vitro and ex vivo. Interestingly, FGF stimulation utilized a non-canonical signaling pathway to activate RSK2 and ATF-1, which was not transduced by EGF stimulation. We confirmed that kaempferol inhibited tyrosine phosphorylation of FGFR, resulted in nuclear accumulation of phospho-ATF-1 at Ser63. Importantly, kaempferol, PKC412, PD98059 and U0126 inhibited EGF-induced anchorage-independent cell transformation in JB6 Cl41 cells. In contrast, FGF-induced cell transformation in soft agar was not inhibited by PD98059 and U0126. Taken together, these results demonstrate that FGF acts as a tumor promoter and dual inhibition of kaempferol on the kinase activities of FGFR and RSK2 suppresses the FGF-induced neoplastic cell transformation through a non-canonical signaling pathway which is not utilized by EGF stimulation. Citation Format: Sun-Mi Yoo, Cheol-Jung Lee, Mee-Hyun Lee, Yong-Yeon Cho. Fibroblast growth factor induces neoplastic cell transformation through a non-canonical signaling pathway. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 39. doi:10.1158/1538-7445.AM2015-39
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