title: Fibroblast growth factor-2 and TPA enhance prostate-cancer-cell proliferation and activate members of the Ras and PKC signal transduction pathways.
abstract: Rat prostate-cancer-cell stable-transfectants expressing either antisense-fibroblast growth factor (FGF-1) or antisense-FGF-2 transcripts that respectively have either undetectable FGF-1 or profoundly diminished FGF-2 protein content, were used for analyses of FGF-2 and/or 12-O-tetradecanoylphorbol 12-acetate (TPA) modulation of cell proliferation. Antisense-FGF-2 transfectant doubling-time was 2.6-fold greater than that of vector-control transfectants. FGF-2 and TPA respectively caused 2.5- and 3.0-fold reductions in antisense-FGF-2 transfectant doubling-time. Culture of antisense-FGF-2 transfectants in medium containing both FGF-2 and TPA further reduced their doubling time; however, this effect was not statistically different from that achieved by TPA treatment alone. Antisense-FGF-1 transfectant doubling-time was 2.2-fold greater than that of vector-control transfectants and was reduced 2.0- or 2.3-fold, respectively, when these cells were cultured in medium containing FGF-2 or TPA. In contrast to the results for antisense-FGF-2 transfectants, culture of antisense-FGF-1 transfectants in medium containing both FGF-2 and TPA caused a 2.6-fold reduction in transfectant doubling-time that was significantly greater than that caused by independent treatment with either FGF-2 or TPA. FGF-2 promoted rapid activation of rat prostate-cancer-cell PKCalpha and PKCepsilon, as assessed by isozyme translocation from the soluble to particulate cell fraction, and only moderately altered PKCdelta distribution. By contrast, TPA promoted rapid activation of all three PKC isozymes. Both the TPA- and FGF-2-mediated PKC activation were prolonged and possibly involved cyclic redistribution of isozymes between soluble and particulate cell fractions. FGF-2 also caused rapid phosphorylation of prostate-cancer-cell Shc, the adapter protein that mediates FGF-receptor-modulated ras signaling. The results of these studies indicate that FGF-2 and TPA independently and conjointly modulate rat prostate-cancer-cell antisense-transfectant doubling time and suggest that effector modulation of rat prostate-cancer-cell proliferation is achieved by processes involving PKC and/or ras mediated signaling.
authors.affiliation: Department of Obstetrics and Gynecology, The University of Texas Health Science Center at San Antonio, 78284-7836, USA.
authors.forename: M
authors.initials: M
authors.lastname: Hrzenjak
authors.forename: S A
authors.initials: SA
authors.lastname: Shain
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects; D016373:DNA, Antisense; D004789:Enzyme Activation; D016220:Fibroblast Growth Factor 1 / Q000096:biosynthesis / Q000502:physiology; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D008297:Male; D011471:Prostatic Neoplasms / Q000473:pathology* / Q000503:physiopathology*; D011493:Protein Kinase C / Q000378:metabolism*; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D051744:Protein Kinase C-epsilon; D051381:Rats; D011994:Recombinant Proteins / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D016373:DNA, Antisense; D007527:Isoenzymes; D011994:Recombinant Proteins; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1; C497260:Prkcd protein, rat; C497257:Prkce protein, rat; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D051744:Protein Kinase C-epsilon; D018631:ras Proteins; D013755:Tetradecanoylphorbol Acetate