months). Both enzymes were negatively expressed in PrECs andPrSCs at mRNA and protein levels. ATX expression was higher than AGK in AILNCaP, DU-145, and PC-3 cell-lines, while AGK was mainly expressed in LNCaP cells. Immunohistochemically, ATX and AGK expressions were negative in non-neoplastic epithelia, while both were weakly expressed in the majority of high-grade intra-epithelial neoplasia (HG-PIN). In cancer foci, ATX and AGK expressions were strong in 49% and 62%, weak in 40% and 32%, and negative in 11% and 6%, respectively. Expressions of both enzymes were significantly correlated with primary Gleason grade of cancer foci (P < 0.0001) and capsular invasion (P = 0.03 and 0.003 respectively). ATX expression was significantly correlated with probability of prostate specific antigen (PSA)-failure after surgery (P < 0.0001). In conclusion, LPA-producing enzymes (ATX and AGK) were frequently expressed in prostate cancer cells and precancerous HG-PIN. In particular, high expression levels of ATX were associated with both malignant potentials and poor outcomes. (Cancer Sci 2009; 100: 1631-1638) L ysophosphatidic acid (1-or 2-acyl-lysophosphatidic acid; LPA) is an extracellular bioactive phospholipid that mediates diverse biological activities including platelet aggregation, smooth muscle contraction, cancer cell proliferation, invasion, angiogenesis, and cytoskeletal reorganization.(1,2) This action is mediated by several interactive mechanisms: (a) It activates RhoA and NF-κβ genes inducing prostate cancer progression. (3,4) (b) It enhances SRE activity in promoters of immediate early growth-related genes.(5) (c) It stimulates secretion of polypeptide growth factors such as EGF (epidermal growth factor) and sensitizes cells to their growth promoting effects.(6,7) (d) Finally, LPA suppresses apoptosis of cancer cells by reducing levels of apoptosispromoting proteins. (8,9) We previously examined LPA activity in various biologic fluids and found a high LPA activity exerted by a specific type of its receptors (Edg-7/LPA3) in human seminal fluids.(10) Furthermore, addition of 18:1 LPA (oleoyl-LPA) to prostate epithelial and stromal cells resulted in up-regulation of a novel extracellular matrix signaling protein CYR-61, that has a growth stimulating potential. (11) Several routes are proposed for LPA production. It is produced extracellularly by lipoprotein oxidation through the action of secretory phospholipase A2 on microvesicles released from activated cells. (12) In plasma, it is produced by thrombin-activated platelets through the stimulated release of phospholipase-A1 and A2 (13) and lysophospholipase D (LysoPLD). (14,15) LysoPLD is identical to autotaxin (nucleotide pyrophosphatase phosphodiesterase-2; ATX/NPP2, EC 3.1.1.5), a cell motility-stimulating factor originally identified in the culture cell supernatant of malignant melanoma cells. (16,17) We previously found that human seminal fluids contain a large amount of ATX, which hydrolyses lysophosphatidylcholine to produce LPA.(18) While LPA signaling had ...

By acting via LPA3, LPA may play an important role in the development of prostate cancer. Switching of LPA receptor expression from LPA3 to LPA1, may be involved in prostate cancer progression and/or androgen independence. LPA may also play a key role in the development of benign prostatic hyperplasia.

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