Autotaxin Implication in Cancer Metastasis and Autoimunne Disorders: Functional Implication of Binding Autotaxin to the Cell Surface

Abstract

Autotaxin (ATX) is an exoenzyme which, due to its unique lysophospholipase D activity, is responsible for the synthesis of lysophosphatidic acid (LPA). ATX activity is responsible for the concentration of LPA in the blood. ATX expression is increased in various types of cancers, including breast cancer, where it promotes metastasis. The expression of ATX is also remarkably increased under inflammatory conditions, particularly in the osteoarticular compartment, where it controls bone erosion. Biological actions of ATX are mediated by LPA. However, the phosphate head group of LPA is highly sensitive to degradation by the action of lipid phosphate phosphatases, resulting in LPA inactivation. This suggests that for efficient action, LPA requires protection, which is potentially achieved through docking to a carrier protein. Interestingly, recent reports suggest that ATX might act as a docking molecule for LPA and also support the concept that binding of ATX to the cell surface through its interaction with adhesive molecules (integrins, heparan sulfate proteoglycans) could facilitate a rapid route of delivering active LPA to its cell surface receptors. This new mechanism offers a new vision of how ATX/LPA works in cancer metastasis and inflammatory bone diseases, paving the way for new therapeutic developments.

Evaluation of serum ATX and LPA as potential diagnostic biomarkers in patients with pancreatic cancer

“…Augmented ATX expression has been reported in breast cancer, PC, hematological cancer, and thyroid and hepatocellular carcinoma [ 15 ]. ATX levels can be correlated with cancer cell invasiveness [ 16 , 17 ].…”

The Role of Epac in Cancer Progression

“…Similarly, Epac has been shown to promote cell invasion and metastasis in in vitro and in vivo fibrosarcoma models by activating Rac1 [80]. Epac/Rap1 and the subsequent activation of Rac1 mediate invadopodia formation by autotaxin (ATX) [80], an exoenzyme that increases aggressiveness and metastasis of many tumors [105][106][107], and lysophosphatidic acid (LPA4) receptor signaling [80]. The pro-migratory effects of Epac have been reported also in breast cancer cells.…”

Expressions and Prognostic Values of LPARs in Human Breast Cancer

“…LPAR1-3 belongs to the endothelium differentiation gene (EDG) receptor, meanwhile LPAR4-6 is a non EDG receptor [6,7] . LPA receptors have seven transmembrane domains, three intracellular loops (intracellular loop-ICL1, ICL2 , ICL3) and three extracellular loops (extracellular loop-ECL1, ECL2, ECL3) [8,9] . At least three kinds of G proteins, Now it's clear that the LPA receptors signal pathway involved at least two Gα subunits (Gαq/11 ， Gα12/13, Gαi/o and GαS) activating different downstream pathways, produce different results under different environments and cell types [10] .…”