Potential action of IGF-1 and EGF on androgen receptor nuclear transfer and transactivation in normal and cancer human prostate cell lines.
This work was designed to determine whether IGF-1 and EGF modulate nuclear transfer and transactivation of the androgen receptor (AR) in human prostate cell lines (PNT1A and DU-145). We first characterized the IGF-1 and EGF receptors by ligand-binding assays with [125I] IGF-1 and [125I] EGF in a normal human prostate epithelial cell line, PNT1A. We then evaluated the effects of these growth factors on AR nuclear transfer and transcriptional activation in this cell line and in DU-145, a human prostate tumor cell line. The cell lines were cotransfected with an AR expression vector and an androgen-responsive luciferase gene driven by the mouse mammary tumor virus (MMTV-luciferase) promoter. Neither IGF-1 nor EGF could activate reporter gene in the absence of androgens. Conversely, both enhanced the magnitude of the AR response in the presence of low levels of androgen (10(-11)-10(-9) M) and this response, increased by twofold, was inhibited by hydroxyflutamide. No effect of IGF-1 and EGF was observed on the intracellular localization of the fusion protein EGFP-AR in either cell line. The fluorescence stayed cytoplasmic even after 24 h of IGF-1 or EGF treatment. Taken together, these data indicate that growth factors are unable to initiate the nuclear translocation of AR in the absence of androgens or to induce ligand-independent transcriptional activity. We observed only cross-talk in the presence of androgens and IGF-1 or EGF, leading to an over-activated AR. In conclusion, the cross-talk between AR and growth factor signaling pathways may sensitize AR to suboptimal stimulation by low levels of androgens.
Orio
Francesco
F
INSERM Unité 439, Pathologie Moléculaire des Récepteurs Nucléaires, 70 rue de Navacelles, Montpellier 34090, France.
Térouanne
Béatrice
B
Georget
Virginie
V
Lumbroso
Serge
S
Avances
Christophe
C
Siatka
Christian
C
Sultan
Charles
C
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D002460:Cell Line; D004815:Epidermal Growth Factor / Q000378:metabolism*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008297:Male; D051379:Mice; D011467:Prostate / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D011944:Receptors, Androgen / Q000378:metabolism*; D015533:Transcriptional Activation
D011944:Receptors, Androgen; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I