RESUMEN
In rat hepatocytes cultured on Matrigel, incubation with epidermal growth factor (EGF) or transforming growth factor-alpha for 24 hr suppressed the constitutive expression of cytochrome P450 (CYP) 2C11 mRNA by 60-70%. The growth factors were maximally effective at concentrations of 10-30 ng/ml. These agents also suppressed the expression of CYP2C11 protein measured 48-72 hr after addition to the medium. Significant suppression of CYP2C11 mRNA was first seen 8 hr after EGF addition to the medium, was maximal by 16 hr, and persisted for at least 36 hr. The suppression of CYP2C11 mRNA by EGF was comparable in magnitude with that produced by interleukin (IL)-1, but greater than that by IL-6. The suppressive effects of EGF and IL-1 on CYP2C11 mRNA were additive, suggesting that the signaling pathways for suppression of CYP2C11 by EGF and IL-1 are different.
Asunto(s)
Hidrocarburo de Aril Hidroxilasas , Sistema Enzimático del Citocromo P-450/genética , Factor de Crecimiento Epidérmico/farmacología , Receptores ErbB/metabolismo , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Microsomas Hepáticos/enzimología , Esteroide 16-alfa-Hidroxilasa , Esteroide Hidroxilasas/genética , Factor de Crecimiento Transformador alfa/farmacología , Animales , Células Cultivadas , Colágeno , Sistema Enzimático del Citocromo P-450/biosíntesis , Familia 2 del Citocromo P450 , Citocinas/farmacología , Regulación hacia Abajo/fisiología , Combinación de Medicamentos , Interferones/farmacología , Laminina , Ligandos , Masculino , Proteoglicanos , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Esteroide Hidroxilasas/biosíntesis , Supresión GenéticaRESUMEN
Enhanced expression of the epidermal growth factor receptor (EGFR) or its ligands, epidermal growth factor (EGF) and transforming growth factor alpha (TGF-alpha) can increase signalling via receptor-mediated pathways which may lead to excessive proliferation and cellular transformation. Such autocrine regulation of growth has been demonstrated for prostate cancer cell lines in culture but its role in prostate cancer in vivo has not been established. To assess the potential of such a mechanism, we have examined the pathway components in prostate carcinomas (CaP) in comparison with non-malignant benign prostatic hyperplasias (BPH). In the present study, we investigate the dosage, structure and expression of EGF, TGF-alpha and EGFR genes in a series of 34 human prostate samples and 3 prostate cancer cell lines. All of the samples contained transcripts from each of the genes. The expression of pre-pro-TGF-alpha mRNA and pre-pro-EGF mRNA were significantly higher in CaP (n = 13) than BPH (n = 21) specimens (p < 0.05). The androgen-responsive prostatic carcinoma cell line, LNCaP, expressed high levels of EGF mRNA while the androgen-independent DU145 and PC-3 cell lines expressed high levels of TGF-alpha mRNA and EGFR mRNA. In general, overexpression of these mRNAs was not associated with amplification or detectable gene rearrangement; only DU145 cells demonstrated any alteration in these genes, with apparent amplification of the TGF-alpha gene. Relative to BPH, all prostate carcinomas and cell lines studied had elevated levels of mRNA for one or both mRNA coding for the ligands for EGFR.(ABSTRACT TRUNCATED AT 250 WORDS)