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Published 12 May 2003. doi:10.1083/jcb.200211099
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© The Rockefeller University Press, 0021-9525/2003/5/547 $5.00
The Journal of Cell Biology, Volume 161, Number 3, 547-556

Article

Androgen-stimulated DNA synthesis and cytoskeletal changes in fibroblasts by a nontranscriptional receptor action



Gabriella Castoria1, Maria Lombardi1, Maria Vittoria Barone2, Antonio Bilancio1, Marina Di Domenico1, Daniela Bottero1, Flavia Vitale1, Antimo Migliaccio1 and Ferdinando Auricchio1

1 Dipartimento di Patologia Generale, Facoltà di Medicina e Chirurgia, II Università degli Studi di Napoli, 80138 Napoli, Italy
2 Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione Giovanni Pascale, 80131 Napoli, Italy

Address correspondence to Ferdinando Auricchio, Dipartimento di Patologia Generale, Facoltá di Medicina e Chirurgia, II Università di Napoli, Via L. De Crecchio 7, Napoli, 80138 Italy. Tel.: 39-081-5665676. Fax: 39-081-291327. E-mail: ferdinando.auricchio{at}unina2.it

In NIH3T3 cells, 0.001 nM of the synthetic androgen R1881 induces and stimulates association of androgen receptor (AR) with Src and phosphatidylinositol 3-kinase (Pl3-kinase), respectively, thereby triggering S-phase entry. 10 nM R1881 stimulates Rac activity and membrane ruffling in the absence of the receptor–Src–PI3-kinase complex assembly. The antiandrogen Casodex and specific inhibitors of Src and PI3-kinase prevent both hormonal effects, DNA synthesis and cytoskeletal changes. Neither low nor high R1881 concentration allows receptor nuclear translocation and receptor-dependent transcriptional activity in fibroblasts, although they harbor the classical murine AR. The very low amount of AR in NIH3T3 cells (7% of that present in LNCaP cells) activates the signaling pathways, but apparently is not sufficient to stimulate gene transcription. This view is supported by the appearance of receptor nuclear translocation as well as receptor-mediated transcriptional activity after overexpression of AR in fibroblasts. In addition, AR-negative Cos cells transiently transfected with a very low amount of hAR cDNA respond to low and high R1881 concentrations with signaling activation. Interestingly, they do not show significant transcriptional activation under the same experimental conditions. Fibroblasts are the first example of cells that respond to steroid hormones with activation of signaling pathways in the absence of endogenous receptor transcriptional activity. The data reported also show that hormone concentration can be crucial in determining the type of cell responsiveness.

Key Words: androgens; nontranscriptional effects; S-phase; membrane ruffling

G. Castoria and M. Lombardi contributed equally to this work.

* Abbreviations used in this paper: AR, androgen receptor; ARE, androgen-responsive element; ERK, extracellular signal–regulated kinase; LBD, ligand-binding domain; MEK-1, MAPK/ERK kinase-1; PgR, progesterone receptor; Pl3-kinase, phosphatidylinositol 3-kinase; p85{alpha}, p85{alpha} wt; Src, Src wt.


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