Abstract
Androgen plays a critical role in regulating the growth and differentiation of normal prostate epithelia, as well as the initial growth of prostate cancer cells. Nevertheless, prostate carcinomas eventually become androgen-unresponsive, and the cancer is refractory to hormonal therapy. To gain insight into the mechanism involved in this hormone-refractory phenomenon, we have examined the potential role of the androgen receptor (AR) in that process. We have investigated the expression of AR and two prostate-specific androgen-responsive antigens, prostatic acid phosphatase (PAcP) and prostate-specific antigen (PSA), for the functional activity of AR in LNCaP and PC-3 human prostate carcinoma cells. Our results are as follows. (i) Clone 33 LNCaP cells express AR, PAcP, and PSA, and cell growth is stimulated by 5alpha-dihydrotestosterone (DHT). Stimulation of cell growth correlates with decreased cellular PAcP activity. (ii) In clone 81 LNCaP cells, the expression of PAcP decreases with a concurrent decrease in the degree of androgen stimulation of cell growth, whereas the expression of PSA mRNA level is up-regulated by DHT, as in clone 33 cells. Conversely, in PAcP cDNA-transfected clone 81 cells, an additional expression of cellular PAcP correlates with an increased stimulation by androgen, higher than the corresponding control cells. (iii) PC-3 cells express a low level of functional AR with no detectable PAcP or PSA, and the growth of PC-3 cells is not affected by DHT treatment. Nevertheless, in two PAcP cDNA-transfected PC-3 sublines, the expression of exogenous cellular PAcP correlates with androgen stimulation. This androgen stimulation of cell growth concurs with an increased tyrosine phosphorylation of a phosphoprotein of 185 kDa. In summary, the data indicate that the expression of AR alone is not sufficient for androgen stimulation of cell growth. Furthermore, in AR-expressing prostate cancer cells, the expression of cellular PAcP correlates with androgen stimulation of cell proliferation.
Highlights
Androgen plays a critical role in regulating the growth and differentiation of normal prostate epithelia, as well as the initial growth of prostate cancer cells
Stimulation of cell growth correlates with decreased cellular prostatic acid phosphatase (PAcP) activity. (ii) In clone 81 LNCaP cells, the expression of PAcP decreases with a concurrent decrease in the degree of androgen stimulation of cell growth, whereas the expression of prostate-specific antigen (PSA) mRNA level is up-regulated by DHT, as in clone 33 cells
androgen receptor (AR) Expression and Androgen Sensitivity to Growth Stimulation—To explore the potential role of AR expression in androgen stimulation of prostate cell growth, we examined the cellular growth of three commonly used human prostate carcinoma cell lines, LNCaP, DU145, and PC-3, after exposure to androgen. 10 nM DHT stimulated the growth of clone 33 LNCaP cells by approximately 1.5–2-fold (Fig. 1A), similar to the original report [27]
Summary
Accumulated to show that steroid-insensitive tumor cells may still express an unchanged level of corresponding receptors. We utilized human prostate carcinoma cell lines including LNCaP and PC-3 cells as model systems to investigate the role of AR expression in the androgen-stimulatory effect on cell growth. We examined PAcP expression because it is an androgen-responsive enzyme [22] and because the cellular PAcP has been implied to be involved in androgen regulation of cell proliferation by participating in the tyrosine phosphorylation signal transduction pathway [22,23,24]. Preliminary results demonstrated that, among different LNCaP cells, the expression of cellular PAcP correlated with androgen responsiveness of cell growth. To explore this correlation further, we examined the effect of androgen on the growth of PAcP cDNA-transfected LNCaP and PC-3 cells
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