ATX-LPA receptor axis in inflammation and cancer

Abstract

Lysophosphatidic acid (LPA, 1- or 2-acyl-sn-glycerol 3-phosphate) mediates a plethora of physiological and pathological activities via interactions with a series of high affinity G protein-coupled receptors (GPCR). Both LPA receptor family members and autotaxin (ATX/LysoPLD), the primary LPA-producing enzyme, are aberrantly expressed in many human breast cancers and several other cancer lineages. Using transgenic mice expressing either an LPA receptor or ATX, we recently demonstrated that the ATX-LPA receptor axis plays a causal role in breast tumorigenesis and cancer-related inflammation, further validating the ATX-LPA receptor axis as a rich therapeutic target in cancer.

Figure 1. Synthetic pathways for LPA and major LPA signaling pathways connecting inflammation and cancer

ATX hydrolyzes lysophospholipids, in particular lysophosphatidylcholine (LPC), to produce bioactive LPA. Newly produced LPA acts on its own GPCRs via at least three distinct classes of heterotrimeric G proteins — Gq, Gi and G12/13 activating multiple downstream pathways and evoke its biological effects, including RAS-ERK pathway through Gi and Gq; PI3K-AKT pathway through Gi; PKC –GSK30β – β-catenin pathway through Gq (and /or Gi); Rho-CDC42 pathway through G12/13; Src-Stat pathway through Gi, which induce expression and activation of multiple transcriptors including STAT3, NF-κB, ATF-2, which induce cell proliferation and production of cytokines. The cytokines bind to their receptors inducing Stat 3 and 5 production and activation.