Exogenous Fibroblast Growth Factors Maintain Viability, Promote Proliferation, and Suppress GADD45{alpha} and GAS6 Transcript Content of Prostate Cancer Cells Genetically Modifi ed to Lack Endogenous FGF-2. Mol Cancer Res

Understanding processes regulating prostate cancer cell survival is critical to management of advanced disease. We used prostate cancer cell transfectants genetically modified to be deficient in either endogenous fibroblast growth factor (FGF-1) or endogenous FGF-2 to examine FGF maintenance of transfectant survival and proliferation and FGF-2-regulated expression of transfectant growth arrest DNA damage (GADD) and growth arrest sequences (GAS) family genes (known modulators of cell cycle progression and survival) and the AS3 gene (an androgen-modulated effector of prostate cell proliferation). When propagated in the absence of exogenous FGFs, FGF-2-deficient transfectants undergo exponential death, whereas FGF-1-deficient transfectants proliferate. Exogenous FGF-1, FGF-2, FGF-7, or FGF-8 promote survival and proliferation of FGF-2-deficient transfectants and enhance FGF-1-deficient transfectant proliferation. Transfectants express FGF receptor FGFR1, FGFR2(IIIb), FGFR2(IIIc), and FGFR3 transcripts, findings consistent with the effects of exogenous FGFs. FGF-2-deficient transfectants express high levels of AS3, GADD45A, GADD45;, GAS8, and GAS11 transcripts and moderate levels of GADD153, GAS2, GAS3, and GAS6 transcripts and lack demonstrable GAS1 or GAS5 transcripts. FGF withdrawal-mediated death of FGF-2-deficient transfectants did not significantly affect cell AS3, GADD153, GADD45;, GAS2, GAS3, GAS7, GAS8, or GAS11 transcript content, whereas GADD45A and GAS6 transcript content was elevated. These studies establish that endogenous FGF-2 dominantly regulates prostate cancer cell survival and proliferation and that exogenous FGFs may assume this function in the absence of endogenous FGF-2. Additionally, we provide the first evidence that FGFs regulate prostate GADD45A and GAS6 transcript content. The latter observations suggest that GADD45A and GAS6 proteins may be effectors of processes that regulate prostate cancer cell survival. Additional studies are required to examine this possibility in detail. (Mol Cancer Res 2004;2(11):653–61