Abstract
Lysophosphatidic acid (LPA) is a bioactive phospholipid with mitogenic and growth factor-like activities affecting cell invasion, cancer progression, and resistance. It is produced mainly by autotaxin and acts on six G-protein-coupled receptors, LPAR1-6. LPA has recently been implicated as a growth factor present in ascites of ovarian cancer patients. However, mitogenic pathways stimulated by LPA via its receptors may involve any novel, thus far uncharacterized, signaling pathway(s). Here we show that three LPA receptors are involved in tumor progression by activation of both the AKT and ERK signaling pathways. CRISPR-edited LPAR2 and LPAR3 knockouts have opposing effects on ERK activation, whereas LPAR6 is involved in the activation of AKT, affecting cell migration and invasion. Our study identifies specific molecular machinery triggered by LPA and its receptors that modulates tumor cells and can serve as therapeutic target in this malignancy.
Highlights
Lysophosphatidic acid (LPA) is a phospholipid produced by autotaxin (ATX) that activates six G-protein-coupled receptors (LPAR1-6) [1,2,3]
Similar to what we found in OVCAR3 cells, ES2 LPAR3KO and LPAR6KO cells had significantly reduced motility compared with control ES2 cells, both in LPA-treated and untreated cells (Figures 4(b) and 4(d)). e results suggest that LPAR3 and LPAR6, but not LPAR2, contribute to motility of ovarian cancer (OC) cells
Our results show that LPAR2 and LPAR3 have opposite effects on the activation of ERK, whereas LPAR6 is responsible for the activation of AKT in OVCAR3 cells
Summary
Lysophosphatidic acid (LPA) is a phospholipid produced by autotaxin (ATX) that activates six G-protein-coupled receptors (LPAR1-6) [1,2,3]. Elucidating the signaling pathway of each LPAR may help in further understanding the ATX-LPA axis and its involvement in OC progression. We reported that LPAR2, LPAR3, and LPAR6 are differentially expressed at different anatomic sites in HGSC and identified a prognostic role for LPAR1, LPAR2, and LPAR5 levels in effusion specimens [21]. Taken together with the finding that the ATX-LPA axis is involved in OC progression and related to disease outcome, our data suggest an important role for LPARs in this malignancy
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