Cellular prostatic acid phosphatase: a protein tyrosine phosphatase involved in androgen-independent proliferation of prostate cancer

Abstract

Human prostatic acid phosphatase (PAcP) was used as a valuable surrogate marker for monitoring prostate cancer prior to the availability of prostate-specific antigen (PSA). Even though the level of PAcP is increased in the circulation of prostate cancer patients, its intracellular level and activity are greatly diminished in prostate cancer cells. Recent advances in understanding the function of the cellular form of PAcP (cPAcP) have shed some light on its role in prostate carcinogenesis, which may have potential applications for prostate cancer therapy. It is now evident that cPAcP functions as a neutral protein tyrosine phosphatase (PTP) in prostate cancer cells and dephosphorylates HER-2/ErbB-2/Neu (HER-2: human epidermal growth factor receptor-2) at the phosphotyrosine (p-Tyr) residues. Dephosphorylation of HER-2 at its p-Tyr residues results in the down-regulation of its specific activity, which leads to decreases in growth and tumorigenicity of those cancer cells. Conversely, decreased cPAcP expression correlates with hyperphosphorylation of HER-2 at tyrosine residues and activation of downstream extracellular signal-regulated kinase (ERK)/mitogen activated protein kinase (MAPK) signaling, which results in prostate cancer progression as well as androgenindependent growth of prostate cancer cells. These in vitro results on the effect of cPAcP on androgen-independent growth of prostate cancer cells corroborate the clinical findings that cPAcP level is greatly decreased in advanced prostate cancer and provide insights into one of the molecular mechanisms involved in prostate cancer progression. Results from experiments using xenograft animal models further indicate a novel role of cPAcP as a tumor suppressor. Future studies are warranted to clarify the use of cPAcP as a therapeutic agent in human prostate cancer patients.

ErbB-2 via PYK2 upregulates the adhesive ability of androgen receptor-positive human prostate cancer cells

“…Additionally, EGF or heregulin had no effect on promoting the adhesive ability of C-33 cells (Supplementary Figure 4). We propose that in androgenindependent, AR-positive PCa cells, ErbB-2 protein is constitutively activated and/or elevated as seen in clinical samples due, in part, to the loss or null of cPAcP expression (Signoretti et al, 2000;Veeramani et al, 2005). In those advanced PCa cells, signal pathways initiated by highly activated ErbB-2 lead to a sustained activation of PYK2 and PYK2-mediated functions, which differs from the transient effect activated by ErbB ligands (Zrihan-Licht et al, 2000;van der Horst et al, 2005;Park et al, 2006).…”

“…Preliminary data showed that in PAcP siRNA oligomertransfected cells, tyrosyl phosphorylation of ErbB-2 and PYK2 increased, higher than that in the scrambled control siRNA oligomer-transfected cells (Veeramani et al, 2005). We established PAcP-knockdown stable subclones in C-33 cells and analysed their adhesion.…”

“…In androgen-independent human PCa cells, ErbB-2 is greatly activated by tyrosyl phosphorylation, at least in part due to the low or null expression of cellular prostatic acid phosphatase (cPAcP), a prostate-unique tyrosine phosphatase that dephosphorylates ErbB-2 . Increased ErbB-2 activity in PCa cells correlated with their androgen-independent proliferation, anchorage-independent growth and tumorigenicity (Igawa et al, 2002;Veeramani et al, 2005;Chen et al, 2007). ErbB-2 may also promote the adhesion of prostate cells (Vafa et al, 1998) while the underlying molecular basis is not understood.…”

Roles of Prostatic Acid Phosphatase in Prostate Cancer

“…PAP는 PSA와 같은 다른 전립선 암 표지자들보다 형태학적 특징과 높은 상관관계를 지니고 있기 때문에 [9], 이를 바탕으 로 PAP는 과거 수십년간 전립선 암의 표지자(marker)로서 혈 청검사와 조직검사에 널리 사용되어 왔다. 이런 표지자로서의 기능과는 다른 측면으로 전립선이 암이 되는 과정에서 cellular PAP 발현의 감소로 인해 탈 인산화가 제대로 일어나지 않아 세포 성장 신호가 지속적으로 유지되는 현상도 밝혀졌다 [20,22,23,38,42]. 즉, cellular PAP 발현의 감소가 전립선 암 발 생 원인중의 하나가 되고, 이 경우 PAP는 tumor supressor의 역할을 하는 것으로 추정된다 [42] (Table 1).…”

“…이런 표지자로서의 기능과는 다른 측면으로 전립선이 암이 되는 과정에서 cellular PAP 발현의 감소로 인해 탈 인산화가 제대로 일어나지 않아 세포 성장 신호가 지속적으로 유지되는 현상도 밝혀졌다 [20,22,23,38,42]. 즉, cellular PAP 발현의 감소가 전립선 암 발 생 원인중의 하나가 되고, 이 경우 PAP는 tumor supressor의 역할을 하는 것으로 추정된다 [42] (Table 1). PAP의 전립선 특 이적 발현의 조절 기작 관련해서도 PAP promoter 부위에서의 cis-acting element들이 몇몇 보고된 바 있지만 [27,29,33,34,50] (Fig.…”