PSA affects prostate cancer cell invasion in vitro and induces an osteoblastic phenotype in bone in vivo

Abstract

BACKGROUND:Patients with advanced prostate cancer frequently have a poor prognosis as a result of metastasis and present with high serum PSA levels. There is evidence suggesting that the serine protease activity of PSA could be involved in the invasion and metastasis of prostate cancer. In this study, we determined the effects of PSA and its precursor, pro-PSA, on invasion and the type of bone metastasis. METHODS:We stably transfected prostate adenocarcinoma cells, human DU-145 and rat MatLyLu, with either the fulllength prepro-PSA sequence or pre-PSA DNA, to generate subclones of cells that secrete pro-PSA or free PSA, respectively. Secretion of PSA was measured by western blot analysis and enzyme-linked immunosorbent assay (ELISA). The invasive and migratory properties of the cells were determined using a basement membrane extract and were compared with corresponding empty vector control cells. Twelve days after injection of PSA-secreting MatLyLu cells into the femora of nude mice, bone tumor burden and histomorphometry were determined using a stereological technique. RESULTS:The transfected cells secreted 0.15-2.23 ng PSA/10 6 cells/day. Pro-PSA-secreting subclones increased invasion and migration by 24-263%. Conversely, the PSA-secreting subclones significantly reduced both invasion and migration by 59-70%. The divergent effects on invasion and migration observed in pro-PSA-and PSA-secreting subclones indicate that different forms of PSA may have different functions. Intrafemoral injections with PSA-secreting MatLyLu cells resulted in an increase in osteoblastic parameters when compared with non-PSA-secreting subclones as measured by bone histomorphometry. Concomitantly, a decrease in osteoclasts and eroded surface was observed.CONCLUSIONS: Our in vitro data suggest that PSA, dependent on the predominant form secreted, may decrease or increase invasive properties of prostate cancer cells. The in vivo results indicate that PSA in the bone microenvironment may contribute to the osteoblastic phenotype of bone metastasis frequently observed in prostate cancer.

Capillarisin blocks prostate‐specific antigen expression on activation of androgen receptor in prostate carcinoma cells

“…The serum PSA levels correlated directly to the disease progression as well as the advancing stages clinically and pathologically, making it as a biomarker for the detection, responses to therapy, and recurrence of prostate cancer . Despite the role as a biomarker, PSA has been demonstrated to promote prostatic tumor growth, migration, and metastasis in both vitro and vivo studies . The expression of the PSA gene is activated by androgen which induced the translocation of AR into the nucleus where it binds to androgen response element (ARE) in the enhancer region of PSA gene …”

“…9 Despite the role as a biomarker, PSA has been demonstrated to promote prostatic tumor growth, migration, and metastasis in both vitro and vivo studies. 10 The expression of the PSA gene is activated by androgen which induced the translocation of AR into the nucleus where it binds to androgen response element (ARE) in the enhancer region of PSA gene. 11 Capillarisin (Cap) is an active component extracted from Artemisia capillaris, in which its young shoots being consumed as vegetables and the whole plant used as an herbal remedy for various inflammatory diseases, such as hepatitis, jaundice cholestasis, and urinary tract infections in Asia.…”

Role of Prostate Specific Antigen (PSA) in Pathogenesis of Prostate Cancer

“…It is synthesized as preproenzymes, proteolytically processed by removal of the signal peptide prior to its secretion as an inactive proenzymes. Pro-PSA is the latent form of the PSA enzyme and has to be activated extracellularly [13]. Processing to obtain the enzymatically active form occurs by further proteolytic removal of a 4 -9 amino acid long peptide at the N-terminus (with the exception of KLK15) [14].…”

A suite of activity-based probes to dissect the KLK activome in drug-resistant prostate cancer

“…The concentration of active and total KLK14 also increased in co-culture compared to LNCaP cells alone, but in contrast to KLK2 and KLK3 this was due to secretion by osteoblasts, suggesting that osteoblasts may contribute to KLK14 activity in bone metastases. KLK2 and KLK3 stimulate osteoblasts to proliferate, differentiate and secrete growth factors through a TGFβdependent mechanism, [43][44][45][46] and these growth factors further enrich the tumor microenvironment and drive pathology in bone metastases. 47,48 Consequently, our data provides support for a KLK activome-mediated double paracrine signaling mechanism that could contribute towards the establishment of PCa-induced osteoblastic lesions (Fig.…”