Prostatic acid phosphatase (PAP) is PI(3)P-phosphatase and its inactivation leads to change of cell polarity and invasive prostate cancer

5239 Prostatic acid phosphatase (PAP) was the first tumor marker of prostate cancer, used for detection of cancer and follow-up of therapy. At tissue level the expression of PAP is decreased with increasing prostate malignancy. The biological function of PAP is nevertheless unknown. To study the physiological function of PAP, mice lacking exon 3 of prostatic acid phosphatase gene (PAP, Acpp) were generated. PAPΔ3/Δ3 mice are fertile. The removal of PAP activity inflicts changes in the prostate in every male mouse in the anterior (AP) and dorsolateral (DLP) lobes. The mice develop prostate hyperplasia followed by initiation of prostate cancer with prostate intraepithelial neoplasia (PIN) and invasive adenocarcinoma. We show that PAP, which is a tyrosine phosphatase, is also a lipid phosphatase and effectively dephosphorylates phosphatidylinositol 3-phosphate (PI(3)P). In DLP PAP co-localizes with PI(3)P subcellularly on the endocytic pathway and intercellularly. Knockout of PAP activity changes the traffic of PAP and increasingly of PI(3)P to the basal domain and the nucleus of cells. We detected increased proliferation and decreased apoptosis in PAP-/- prostates. Changes at subcellular level took place early after sexual maturation in PAP-/- prostates. Also gene expressions were remarkably changed. Gene expression analyses were made from total prostates of one and six-month-old mice and from DLP at the age of two months. Main gene expressions changes were in categories: transcription factors, kinase activity, hydrolase activity, receptor activity and ion channel/transport. PI3K/Akt-signaling was also changed in PAP-/- epithelium. Our results show that PAP is not only an important regulator of PI(3)P transport, but also a novel tumor suppressor of prostate epithelial cells.