The ATX-LPA-LPAR1 signaling pathway plays a universal role in stimulating diverse cellular responses, including cell proliferation, migration, survival, and invasion in almost every cell type. The ATX-LPAR1 axis is linked to several metabolic and inflammatory diseases including cancer, fibrosis, and rheumatoid arthritis. Numerous selective ATX or LPAR1 inhibitors have been developed and so far, their clinical efficacy has only been evaluated in idiopathic pulmonary fibrosis. None of the ATX and LPAR1 inhibitors have advanced to clinical trials for cancer and rheumatoid arthritis. Nonetheless, several research groups, including ours, have shown considerable benefit of simultaneous ATX and LPAR1 inhibition through combination therapy. Recent research suggests that dual-targeting therapies are superior to combination therapies that use two selective inhibitors. However, limited reports are available on ATX-LPAR1 dual inhibitors, potentially due to co-expression of multiple different LPARs with close structural similarities at the same target. In this review, we discuss rational design and future directions of dual ATX-LPAR1 inhibitors.
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.
Autotaxin (ENPP2/ATX) and lysophosphatidic acid (LPA) receptors represent two key players in regulating cancer progression. The present study sought to understand the mechanistic role of LPA G protein-coupled receptors (GPCR), not only in the tumor cells but also in stromal cells of the tumor microenvironment. B16F10 melanoma cells predominantly express LPA5 and LPA2 receptors but lack LPA1. LPA dose dependently inhibited invasion of cells across a Matrigel layer. RNAi-mediated knockdown of LPA5 relieved the inhibitory effect of LPA on invasion without affecting basal invasion. This suggests that LPA5 exerts an anti-invasive action in melanoma cells in response to LPA. In addition, both siRNA-mediated knockdown and pharmacologic inhibition of LPA2 reduced the basal rate invasion. Unexpectedly, when probing the role of this GPCR in host tissues, it was found that the incidence of melanoma-derived lung metastasis was greatly reduced in LPA5 knockout (KO) mice compared with wild-type (WT) mice. LPA1-KO but not LPA2-KO mice also showed diminished melanoma-derived lung metastasis, suggesting that host LPA1 and LPA5 receptors play critical roles in the seeding of metastasis. The decrease in tumor cell residence in the lungs of LPA1-KO and LPA5-KO animals was apparent 24 hours after injection. However, KO of LPA1, LPA2, or LPA5 did not affect the subcutaneous growth of melanoma tumors.These findings suggest that tumor and stromal LPA receptors, in particular LPA1 and LPA5, play different roles in invasion and the seeding of metastasis.
<p>Supplementary Figure 4. Effect of BMP22 on the basal invasion of B16F10 cells across a matrigel layer. Data are representative of an experiment performed twice in quadruplicates and are expressed as mean {plus minus} SD. *Denotes p value < 0.05 using one-way ANOVA followed by a Bonferroni post-test.</p>
<p>Supplementary Figure 2. LPA1-5 receptor profiling in whole lung tissue isolated from WT, LPA1-, LPA2- and LPA5KO mice, respectively using quantitative real-time PCR. Data are expressed as mean {plus minus} SEM (n = 3 mice).</p>
Abstract ATX, a lysophospholipase D that generates LPA, is highly up-regulated in metastatic and chemotherapy-resistant carcinomas. Many cancers secrete ATX, and it contributes to their invasive properties. LPA produced by ATX activates LPA1-8 G protein-coupled receptors on the cell surface. Many cancers over-express multiple subtypes of LPAR and the overexpression of LPAR leads to malignant transformation, metastasis, and resistance to therapy. Therefore, ATX-LPA signaling axis is an emerging target for cancer therapy. We have previously shown that knockdown of ATX expression in B16F10 melanoma cells decreased tumor invasion in vitro and metastasis in vivo. In this study, we sought to understand the roles of the LPA GPCRs both in the tumor cells and tissues targeted by metastatic cancer cells. Using the in vivo B16 melanoma metastasis model syngeneic to the C57BL/6 mouse strain, we found that the incidence of lung metastasis was greatly reduced in the LPA5KO mice compared to WT, LPA1KO, and LPA2KO mice, respectively. In addition, we found that the selective inhibitor of LPA1&3, Ki16425 also reduced lung metastasis, suggesting that inhibition of LPA5 and LPA1 receptors in the target tissues may prevent cancer metastasis. B16 melanoma cells predominantly express LPA5 receptor. These cells do not invade across a matrigel layer in response to LPA. We found that siRNA knockdown of LPA5 receptors in B16 melanoma cells relieves this inhibition and resulted in an increase in invasion. These results suggest that the LPAR, in particular LPA5 receptors in tumor and stromal cells may play different roles in invasion and metastasis. Citation Format: Gabor Tigyi, Yuko Fujiwara, SueChin Lee, Jianxiong Liu, Renukadevi Patil, Renuka Gupte, Duane D. Miller, Tamas Oravecz, Louisa Balazs. Targeting ATX and LPA receptors melanoma invasion and metastasis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3884. doi:10.1158/1538-7445.AM2013-3884
