Controlling cancer through the autotaxin–lysophosphatidic acid receptor axis

Abstract

LPA (lysophosphatidic acid, 1-acyl-2-hydroxy-sn-glycero-3-phosphate), is a growth factor-like lipid mediator that regulates many cellular functions, many of which are unique to malignantly transformed cells. The simple chemical structure of LPA and its profound effects in cancer cells has attracted the attention of the cancer therapeutics field and drives the development of therapeutics based on the LPA scaffold. In biological fluids, LPA is generated by ATX (autotaxin), a lysophospholipase D that cleaves the choline/serine headgroup from lysophosphatidylcholine and lysophosphatidylserine to generate LPA. In the present article, we review some of the key findings that make the ATX–LPA signalling axis an emerging target for cancer therapy.

Hits of a High-Throughput Screen Identify the Hydrophobic Pocket of Autotaxin/Lysophospholipase D As an Inhibitory Surface

“…6C) caused a significant reduction in the metastatic nodules in the pretreatment paradigm but did not reach significance in the post-inoculation paradigm (P 5 0.056). Novel Inhibitory Surface in Autotaxin 4-Pentadecyl benzylphosphonic acid, which is also a dual-type inhibitor, caused a significant reduction in the number of metastatic nodules in the lungs (Gupte et al, 2010;Gotoh et al, 2012). Altogether, these findings support the hypothesis that inhibition of the ATX hydrophobic pocket can have similar blocking effects of melanoma metastasis in vivo as inhibiting the ATX active site.…”

“…After injection into C57BL/6 mice via the tail vein, the syngeneic B16-F10 melanoma cells metastasize primarily to the lungs in an ATX-dependent manner (Baker et al, 2006;Gupte et al, 2011;Gotoh et al, 2012). We showed that in this model administration of an ATX inhibitor up to 48 hours postinoculation of the melanoma cells still causes a significant reduction in the number of metastatic lung nodules, indicating a role for ATX in the colonization and seeding of the lungs with melanoma cells (Gotoh et al, 2012). We tested compounds 1 and 3 by treating mice 1 day prior or 1 day after inoculation of B16-F10 melanoma cells via the tail vein, and continued for an additional 10 days.…”

“…At the present time there is no approved ATX inhibitor available for therapy; however, development of ATX inhibitors has gained increasing interest with several smallmolecule ATX inhibitors having been described (Ferry et al, 2008;Saunders et al, 2008;Albers et al, 2010;Gierse et al, 2010;Hoeglund et al, 2010;Mize et al, 2011;Gotoh et al, 2012;Kawaguchi et al, 2013;St-Coeur et al, 2013). A considerable amount of effort has been devoted to the characterization of inhibitors that interact with the active site of ATX.…”

Recent advances in targeting the autotaxin-lysophosphatidate-lipid phosphate phosphatase axis in vivo

“…The initial relation of ATX/LPA signaling with melanoma cells resulted in much of the early research into ATX being concentrated in the cancer field [39,[57][58][59][60][61][62][63][64][65] . LPA increases vascular endothelial growth factor (VEGF) production, which stimulates angiogenesis [66] , a process necessary for tumor progression.…”

The status of the lysophosphatidic acid receptor type 1 (LPA1R)

“…Finally, it is well known that LPA signalling inuences cancer-related processes, 63 especially via LPA 2 . Nevertheless, there is also evidence of LPA 1 implication in cancer progression, specically in ovarian, breast and gastrointestinal ones.…”