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  • ATX LPA signaling in cancer is also well known

    2024-05-23

    ATX/LPA signaling in cancer is also well known to promote chemotherapy and radiotherapy resistance [7]. Furthermore, others have recently shown that endothelial-derived ATX activity in renal cell carcinoma promotes renal tumorgenesis and acquired resistance to sunitinib through an IL-8-mediated mechanism [162]. ATX/LPA signaling is physiologically response to promote wound-healing following injury. Significantly, cytotoxic cancer therapy and ionizing radiation essentially produce an injury to the tumor and adjacent tissues. In the process of self-repair, affected tissues use ATX/LPA signaling to increase the expression of survival pathways, which reduces the subsequent effectiveness of the therapy. Hence, inhibiting ATX production of LPA should block this vicious cycle of injury and tissue repair and therefore have great utility in abrogating cancer therapy resistance.
    Development and implementation of ATX inhibitor therapies As an extracellular enzyme, ATX is a very attractive drug target. Considerable attention has been given towards designing potent inhibitors of ATX, and this has been reviewed previously [55], [163], [164]. We will now discuss only those inhibitors that have been used primarily in vivo. We will begin by summarizing ATX targeting strategies through indirect means, the development of both lipid- and non-lipid competitive ATX inhibitors and the current methods being employed to develop more effective ATX inhibitors.
    Perspective and concluding remarks
    Conflict of interest
    Acknowledgements
    Introduction Rheumatoid arthritis (RA) is a chronic, inflammatory, and systemic autoimmune disease that affects peripheral joints with a symmetric distribution. RA is characterized by chronic synovial inflammation that leads to the progressive destruction of cartilage and bone (Feldmann et al., 1996, Firestein, 2003, Klareskog et al., 2009). Within the peripheral joints, a severe inflammatory process leads to synovial hyperplasia that is caused by the proliferation of resident fibroblast-like synoviocytes and the recruitment of additional inflammatory cell-types. The infiltrating Fructose sale then produce a wide range of cytokines and chemokines that maintain a state of chronic inflammation within the joint that can lead to the destruction of the joint architecture without treatment (Feldmann et al., 1996, Firestein, 2003, Klareskog et al., 2009). Recent studies have demonstrated the involvement of the ATX–LPA (Autotaxin–lysophosphatidic acid) pathway in the pathogenesis of RA. ATX is a secreted lysophospholipase D that produces LPA by cleaving the choline group from lysophosphatidylcholine (LPC). The increased expression of both ATX and LPA has been reported in synovial fluid and fibroblasts like synoviocytes (FLS), from RA patients (Santos et al., 1996, Kehlen et al., 2001; Nikitopoulo et al., 2012; Miyabe et al., 2013; Nochi et al., 2008). Several research groups have analysed the function of LPA in RA FLS. Nochi et al. described that LPA induced cytokines and COX-2 production in RA FLS. Additionally, Orosa et al. demonstrated that LPA receptor inhibition induced apoptosis in these cells. It has also been described that the genetic deletion of the LPA1 receptor (Miyabe et al., 2013), ATX (Nikitopoulou et al., 2012) genes or LPA receptor inhibition (Orosa et al., 2012) reduced the severity of experimental arthritis. In this review we summarise the current literature of the ATX–LPA pathway in RA.
    Synthesis and function of lysophosphatidic acid ATX was initially identified in 1992 in human melanoma cells as a potent inducer of motility (Stracke et al., 1992). Ten years later, Tokumora et al. and Umezu-Goto et al. purified lysophospholipase D from plasma and foetal calf serum. They showed that this enzyme corresponded to ATX. ATX cleaves the choline group from lysophosphatidylcholine to produce the majority of extracellular LPA. This finding was demonstrated using heterozygous mice for Enpp2, which is the gene encoding ATX. The plasma ATX levels in these mice were reduced by 50% (van Meeteren et al., 2006, Tanaka et al., 2006). Furthermore, the transgenic ATX mice had a 2-fold increase in their plasma ATX levels (Pamuklar et al., 2009). In contrast, it has been reported that intracellular LPA is produced by the deacylation of phosphatidic acid by phospholipase A1 and A2 (PLA1, PLA2) (Aoki et al., 2008).