Abstract
BACKGROUND AND PURPOSE:
Highly vascularized ovarian carcinoma secretes the putative endocannabinoid and G-protein coupled receptor 55 (GPR55) ligand L-α-lysophosphatidylinositol (LPI) into the circulation. We aimed to elucidate the involvement of LPI/GPR55 in ovarian cancer angiogenesis.
EXPERIMENTAL APPROACH:
Secretion of LPI by three ovary cancer cell lines (OVCAR-3, OVCAR-5 and COV-362) was tested by mass spectrometery. 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, migration of neonatal and adult human endothelial colony-forming cells (ECFCs). Engagement of GPR55 was verified by using its pharmacological inhibitor CID16020046 and diminution of GPR55 expression by four respective target-specific siRNAs. To study underlying signal transduction Western blot analysis were performed.
KEY RESULTS:
Ovarian carcinoma cell-derived LPI stimulated angiogenesis in the CAM assay. Applied LPI stimulated proliferation, network-formation, migration of neonatal and ECFCs in vitro and angiogenesis in the in vivo CAM. The pharmacological GPR55-inhibitor CID16020046 inhibited LPI-stimulated ECFC proliferation, network-formation and migration in vitro as well as ovarian carcinoma cells- and LPI-induced angiogenesis in vivo. Four target-specific siRNAs against GPR55 prevented the effect of LPI on angiogenesis. These pro-angiogenic effects of LPI where induced by GPR55-dependent phosphorylation of ERK1/2 and p38 kinase.
CONCLUSIONS AND IMPLICATIONS:
We conclude that inhibiting the pro-angiogenic LPI/GPR55-pathway appears a promising target against angiogenesis in ovarian carcinoma.
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- PMID:
- 25989290
- [PubMed – as supplied by publisher]
