Exogenous fibroblast growth factors maintain viability, promote proliferation, and suppress GADD45alpha and GAS6 transcript content of prostate cancer cells genetically modified to lack endogenous FGF-2.
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, GADD45alpha, GADD45gamma, 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, GADD45gamma, GAS2, GAS3, GAS7, GAS8, or GAS11 transcript content, whereas GADD45alpha 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 GADD45alpha and GAS6 transcript content. The latter observations suggest that GADD45alpha and GAS6 proteins may be effectors of processes that regulate prostate cancer cell survival. Additional studies are required to examine this possibility in detail.
Shain
Sydney A
SA
Department of Obstetrics and Gynecology, University of Texas Health Science Center, 7703 Floyd Curl Drive, MSC 7836, San Antonio, TX 78229-7836, USA. shains@uthscsa.edu
D000818:Animals; D002452:Cell Count; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D015536:Down-Regulation / Q000235:genetics; D016220:Fibroblast Growth Factor 1 / Q000235:genetics / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000235:genetics* / Q000494:pharmacology*; D051523:Fibroblast Growth Factor 7; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D016372:RNA, Antisense / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014407:Tumor Cells, Cultured; D000099255:Growth Arrest-Specific Protein 6; D000097642:GADD45 Proteins
D018797:Cell Cycle Proteins; D016220:Fibroblast Growth Factor 1; D016222:Fibroblast Growth Factor 2; D051523:Fibroblast Growth Factor 7; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D016372:RNA, Antisense; D012333:RNA, Messenger; D000099255:Growth Arrest-Specific Protein 6; C496453:FGF7 protein, human; C496456:FGF8 protein, human; C496455:Fgf7 protein, rat; C496458:Fgf8 protein, rat; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C499073:Gadd45a protein, rat