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

Abstract

Extracellular lysophosphatidate (LPA) is a potent bioactive lipid that signals through six G-protein-coupled receptors. This signaling is required for embryogenesis, tissue repair and remodeling processes. LPA is produced from circulating lysophosphatidylcholine by autotaxin (ATX), and is degraded outside cells by a family of three enzymes called the lipid phosphate phosphatases (LPPs). In many pathological conditions, particularly in cancers, LPA concentrations are increased due to high ATX expression and low LPP activity. In cancers, LPA signaling drives tumor growth, angiogenesis, metastasis, resistance to chemotherapy and decreased efficacy of radiotherapy. Hence, targeting the ATX-LPA-LPP axis is an attractive strategy for introducing novel adjuvant therapeutic options. In this review, we will summarize current progress in targeting the ATX-LPA-LPP axis with inhibitors of autotaxin activity, LPA receptor antagonists, LPA monoclonal antibodies, and increasing low LPP expression. Some of these agents are already in clinical trials and have applications beyond cancer, including chronic inflammatory diseases.

LPP3 mediates self-generation of chemotactic LPA gradients by melanoma cells

“…These findings present an interesting potential target for anti-metastatic therapy when treating melanoma. Interestingly, LPP1 and LPP3 have been targeted in potential therapies for ovarian cancer ( Tanyi et al, 2003 b ; Benesch et al, 2016 ). However, these therapies aimed to increase LPP expression in order to reduce overall LPA levels, thereby diminishing its pro-tumourigenic effects.…”

Genetic deletion of Autotaxin from CD11b+ cells decreases the severity of experimental autoimmune encephalomyelitis

“…4B), while there was no correlation with the corresponding LPA species (Fig S1A). No significant changes in the mRNA profile of PLPPs, largely responsible for extracellular LPA degradation [31], were noted ( Fig. 4C), suggesting minor involvement in the regulation of spinal cord LPA levels in EAE.…”

Lipin proteins and glycerolipid metabolism: Roles at the ER membrane and beyond

“…It is thought that a major portion of LPP activity may be carried out at the cell surface, where they hydrolyze extracellular lysophosphatidic acid or sphingosine-1-P and the resulting products activate intracellular signaling cascades in neighboring cells [16,50]. This ecto-enzymatic activity of LPPs may have a role in embryogenesis, tissue repair, development of atherosclerosis, and tumor growth and metastasis [51,52]. At intracellular membranes, LPPs have the potential to hydrolyze lipid substrates on the luminal side of ER or Golgi membranes, whereas lipin PAP activity acts at the cytosolic surface of these membranes.…”