The GPR 55 agonist, L‐α‐lysophosphatidylinositol, mediates ovarian carcinoma cell‐induced angiogenesis

Background and Purpose Highly vascularized ovarian carcinoma secretes the putative endocannabinoid and GPR 55 agonist, L ‐α‐lysophosphatidylinositol ( LPI ), into the circulation. We aimed to assess the involvement of this agonist and its receptor in ovarian cancer angiogenesis. Experimental Approach Secretion of LPI by three ovarian cancer cell lines ( OVCAR ‐3, OVCAR ‐5 and COV ‐362) was tested by mass spectrometry. Involvement of cancer cell‐derived LPI on angiogenesis was tested in the in vivo chicken chorioallantoic membrane ( CAM ) assay along with the assessment of the effect of LPI on proliferation, network formation, and migration of neonatal and adult human endothelial colony‐forming cells ( ECFCs ). Engagement of GPR 55 was verified by using its pharmacological inhibitor CID 16020046 and diminution of GPR 55 expression by four different target‐specific siRNAs . To study underlying signal transduction, Western blot analysis was performed. Key Results Ovarian carcinoma cell‐derived LPI stimulated angiogenesis in the CAM assay. Applied LPI stimulated proliferation, network formation, and migration of neonatal ECFCs in vitro and angiogenesis in the in vivo CAM . The pharmacological GPR 55 inhibitor CID 16020046 inhibited LPI ‐stimulated ECFC proliferation, network formation and migration in vitro as well as ovarian carcinoma cell‐ and LPI ‐induced angiogenesis in vivo . Four target‐specific siRNAs against GPR 55 prevented these effects of LPI on angiogenesis. These pro‐angiogenic effects of LPI were transduced by GPR 55‐dependent phosphorylation of ERK 1/2 and p38 kinase. Conclusions and Implications We conclude that inhibiting the pro‐angiogenic LPI / GPR 55 pathway appears a promising target against angiogenesis in ovarian carcinoma.