Neither fibroblast growth factor-1 nor fibroblast growth factor-2 is an androgen receptor coactivator in androgen-resistant prostate cancer.
We used rat prostate cancer cell stable transfectants that lacked either endogenous fibroblast growth factor (FGF)-1 secondary to constitutive expression of FGF-1 antisense RNA (aFa2-transfectants) or endogenous FGF-2 isoforms secondary to constitutive expression of FGF-2 antisense RNA (bFa9-transfectants) to examine the potential synergistic effects of mitogen and androgen as modulators of proliferation. During culture on 5% charcoal-stripped fetal bovine serum (CS-FBS), FGF-1 caused a 2- to 2.5-fold increase in the proliferation of aFa2-transfectants that lacked endogenous FGF-1 and retained full expression of FGF-2 isoforms. In marked constrast, bFa9-transfectants that lacked FGF-2 isoforms and retained full expression of FGF-1 died with exponential kinetics when cultured on either 5% CS-FBS or 5% FBS in the absence of FGF-2. However, FGF-2 promoted bFa9-transfectant survival and exponential proliferation during culture on either 5% CS-FBS or 5% FBS. The nonmetabolizable androgen R1881 did not affect proliferation of either the aFa2- transfectants, the bFa9-transfectants, or the parental prostate cancer cells used to generate these transfectants. Additionally, neither of the androgen receptor antagonists RU23908 or bicalutamide affected either FGF-1-mediated aFa2-transfectant proliferation or FGF-2-mediated bFa9-transfectant proliferation during culture on 5% CS-FBS. Notably, transient transfection analyses established R1881 concentration-dependent induction of chloramphenicol acetyltransferase activity in both aFa2-transfectants and bFa9-transfectants. Thus, the failure of either androgen or antiandrogen to affect either FGF-mediated or FGF-independent antisense-transfectant proliferation is not attributable to absence of functional androgen receptors. The results indicate that FGF effects in these androgen-resistant antisense transfectants do not involve either androgen-dependent or androgen-independent, mitogen-mediated androgen receptor activation. Our studies show that these rat prostate cancer cells are characterized by both retention of functional androgen receptors during development of androgen resistance and mitogen-mediated, autocrine or paracrine (or both) modulated proliferation. These are two prominent properties characteristic of advanced human prostate cancer.
Shain
S A
SA
Department of Obstetrics and Gynecology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-7836, USA. shains@uthscsa.edu
D000726:Androgen Antagonists / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016895:Culture Media, Serum-Free; D016220:Fibroblast Growth Factor 1 / Q000494:pharmacology / Q000502:physiology*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048289:Imidazolidines; D008297:Male; D015741:Metribolone / Q000494:pharmacology; D009570:Nitriles; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D045165:Testosterone Congeners / Q000494:pharmacology; D014105:Tosyl Compounds; D014162:Transfection; D014407:Tumor Cells, Cultured
D000726:Androgen Antagonists; D000813:Anilides; D016895:Culture Media, Serum-Free; D007093:Imidazoles; D048289:Imidazolidines; D009570:Nitriles; D011944:Receptors, Androgen; D045165:Testosterone Congeners; D014105:Tosyl Compounds; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1; D015741:Metribolone; C021277:nilutamide; C053541:bicalutamide