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  • Five alternatively spliced isoforms of ATX have been

    2023-11-20

    Five alternatively-spliced isoforms of ATX have been described and all are catalytically active [16], [17]. The original ATX described in 1992 is termed ATXα, whereas the most abundant isoform is ATXβ and is the same isoform responsible for plasma lysoPLD activity [18]. Full length ATX is synthesized as a pre-proenzyme and is secreted by the classical secretory pathway [19], [20]. Secreted ATX binds to integrin or heparan sulfates on the cell surface through its somatomedin-B-like (SMB) domains, which function independently of its catalytic domain. This binding is believed to localize LPA production adjacent to LPA receptors. The identity of the cell-surface binding partner varies with cell type and is described elsewhere [21], [22], [23], [24], [25]. This remains an area of active investigation. The crystal structures of mouse and rat ATX were solved in 2011 and have revealed much about the catalytic site of ATX [22], [26]. ATX has a preference for unsaturated and polyunsaturated substrates [26]. There is a hydrophobic pocket in the catalytic domain, which is slightly U-shaped, and this is able to accommodate the kinked acyl chains of unsaturated fatty acids compared to extended linear conformations of saturated fatty acids [26]. Although there are other enzymatic processes that can generate LPA such as the actions of secretory phospholipase A2 (sPLA2) or Ca2+-independent phospholipase A2 (iPLA2β) on phosphatidate (PA) [27], [28], [29], ATX is the major contributor of extracellular LPA. Levels of circulating LPA are decreased by about 50% in mice carrying a heterozygous null-mutation for ATX [30], [31]. Further, the contribution of ATX to maintaining circulating LPA is demonstrated since its inhibition causes a rapid decrease in plasma LPA of >95% [12], [32], [33]. The initial relation of ATX/LPA signaling with melanoma Cyprodime hydrochloride resulted in much of the early research into ATX being concentrated in the cancer field, and progress has been regularly reviewed [34], [35], [36], [37], [38], [39], [40], [41], [42], [43]. In short, LPA signaling through at least six known G-protein-coupled receptors (LPA1-6) stimulates cell survival and migration through the relative activations of phosphatidylinositol 3-kinase (PI3K), ERK1/2, mTOR, Ca2+-transients, Rac, Rho and Ras (Fig. 1B) [44]. LPA increases vascular endothelial growth factor (VEGF) production, which stimulates angiogenesis [45], a process necessary for tumor progression. LPA decreases the expression of the tumor suppressor, p53 [46], thus increasing cancer cell survival and division. LPA levels as high as 10μM have been found in ascites fluid of advanced ovarian cancer patients [8]. Mice that overexpress ATX, LPA1, LPA2 or LPA3 in mammary epithelium develop spontaneous metastatic mammary tumors [47]. Further, ATX is among the top 40 most up-regulated genes in metastatic cancers [48]. We discovered that LPA produces resistance to the cytotoxic effects of paclitaxel, a first line treatment for breast cancer [49], [50]. This was confirmed [51] and extended to carboplatin resistance [52]. ATX and LPA also protect against radiation-induced cell death [7], [53]. Throughout these studies, a common conclusion is that blocking the production of LPA by ATX could be a novel therapeutic intervention for attenuating therapy resistance [7], [44], [54], [55], [56], [57], [58], [59], [60]. The findings from the cancer field have been translated to other disease models with inflammation being a common factor [6], [9], [61], [62], [63], [64], [65], [66], [67], [68], [69]. The ATX/LPA signaling pathway is involved in chronic inflammatory conditions, and for some patients, inflammation could underlie the development and progression of their cancers. This is best understood in colon cancer models where chronic inflammation of colonic mucosa leads to dysplasia and eventual cancer [70], [71], [72]. We will summarize current knowledge on the embryologic and physiologic roles of ATX and contrast this to the roles of ATX in inflammation-mediated diseases, including cancer. We will also discuss current progress on the development of ATX inhibitor therapies and offer insights into the future directions of the field. A new model for ATX production in carcinomas will also be proposed.