ErbB-2 signaling is involved in regulating PSA secretion in androgen-independent human prostate cancer LNCaP C-81 cells

Abstract

The expression and secretion of prostate-specific antigen (PSA) are regulated by androgens in normal prostate secretory epithelial cells. In prostate cancer patients, the serum PSA level is usually elevated and cancer cells are initially responsive to androgens. However, those cancer cells become androgen-independent after androgen ablation therapy. In hormone-refractory cancer patients, even in an androgen-deprived environment, the circulation level of PSA rebounds and is constitutively elevated through a yet unknown mechanism. Tyrosine phosphorylation of ErbB-2 is involved in regulating the androgen-responsive phenotype of prostate cancer cells, and it is at least partly regulated by the cellular form of prostatic acid phosphatase (PAcP), a prostate-unique protein tyrosine phosphatase. We investigated the ErbB-2 signal pathway in androgen-independent PSA secretion. LNCaP C-81 cells, which are androgen-independent LNCaP cells lacking endogenous PAcP expression with a hypertyrosine phosphorylated ErbB-2, secreted a higher level of PSA in conditioned media than did androgen-sensitive LNCaP C-33 parental cells. A restored expression of cellular PAcP in C-81 cells was concurrent with a decrease in tyrophosphorylation of ErbB-2 and reduction of PSA secretion. Moreover, transient transfection of C-33 cells with the wild-type ErbB-2 or a constitutively active mutant of MEK1 cDNA resulted in an increased level of secreted PSA. The elevation of secreted PSA level by the forced expression of ErbB-2 was inhibited by an MEK inhibitor, PD98059. In C-81 cells, the expression of a dominant negative mutant of ErbB-2 reduced the secreted level of PSA. The inhibition of ErbB-2 or mitogenactivated protein (MAP) kinases by specific inhibitors AG879, AG825, or PD98059 led to a decrease in PSA secretion. Taken together, our data clearly indicate that the ErbB-2 signal pathway via MAP kinases (ERK1/2) is involved in regulating the secretion of PSA by androgenindependent human prostate cancer LNCaP C-81 cells in an androgen-depleted environment.

Regulator of G-protein signaling 2 (RGS2) inhibits androgen-independent activation of androgen receptor in prostate cancer cells

“…As shown in Figure 6a (lower panel), the level of active ERK1/2 (phosphorylated) in LNCaP-C81 cells was significantly higher compared to LNCaP-C33 cells, consistent with the previous reports that ERKs were activated in androgen-independent LNCaP cells in the absence of exogenous androgen (Lee et al, 2003;Unni et al, 2004). Expression of RGS2 or treatment of MEK inhibitor U0126 strongly decreased the level of active ERK1/2 (phosphorylated) in LNCaP-C81 cells.…”

“…ERK1/2 mediate the inhibition of androgen-independent AR activity by RGS2 in LNCaP cells Since the mitogen-activated protein kinase (MAPK), particularly the ERK signaling pathway, plays an important role in prostate cancer progression (Gioeli et al, 1999;Bakin et al, 2003) and ERK1/2 are constitutively activated in high-passage androgenindependent LNCaP cells (Lee et al, 2003;Unni et al, 2004), we investigated the role of ERK signaling pathway in G q -mediated activation of AR. G q Q209L RGS2 inhibits androgen receptor X Cao et al plasmid was transfected into LNCaP-C33 cells without or with RGS2 or RGS2N149A plasmids and the level of active ERK1/2 (phosphorylated) in cell lysates was determined by Western blot assay using antiphosphorylated ERK1/2 antibody.…”

“…However, the lowpassage LNCaP cells (C33) grow slowly in an androgen-sensitive manner, whereas high-passage (C81) cells grow aggressively and also become androgen-independent even though they are still androgen-responsive. This tumor cell model closely resembles the two stages of tumorigenesis with the acquisition of hormonerefractiveness as seen in prostate cancer patients (Karan et al, 2001Denmeade et al, 2003) and is useful in studying the progressive changes in the primary and metastatic stages of prostate cancer (Karan et al, 2001;Lee et al, 2003;Lin et al, 2003;Unni et al, 2004).…”

Androgen signaling is required for the vitamin D-mediated growth inhibition in human prostate cancer cells

“…Meanwhile, it was also demonstrated that 1,25-VD can inhibit the growth of an androgenindependent prostate cancer derivative of LNCaP (LNCaP-104R1), even in the absence of androgen, and that the growth inhibition was not blocked by Casodex (Yang et al, 2002). However, during the development of androgen independence in prostate cancer, some mitogenic pathways, such as epidermal growth factor (EGF) receptor, ErbB-2, mitogen-activated protein kinases, and transforming growth factor-a (TGF-a) signaling, are upregulated and crosstalk with androgen signaling in regulating androgen-independent prostate cancer growth (Myers et al, 1999;Lee et al, 2003). Therefore, Casodex might not be sufficient to block AR actions at this stage.…”

Tyrosine-317 of p52Shc mediates androgen-stimulated proliferation signals in human prostate cancer cells

“…Interestingly, in androgen-independent human LNCaP C-81, PC-3 and DU 145 prostate cancer cells, ErbB-2 protein is tyrosine hyper-phosphorylated with an activated specific activity, while the ErbB-2 protein level is not elevated (Lin and Meng, 1996;Meng and Lin, 1998). In C-81 cells, the highly tyrosine-phosphorylated ErbB-2 correlates with androgen-independent growth and PSA secretion Meng et al, 2000;Lee et al, 2003). The molecular mechanism of this tyrosine phosphorylation signal pathway involving in androgen action requires further elucidation.…”