Antiangiogenic Action of JZL184 on Endothelial Cells via Inhibition of VEGF Expression in Hypoxic Lung Cancer Cells
JZL184, an inhibitor of monoacylglycerol lipase (MAGL) and thus of the degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG), mediates various anticancer effects in preclinical studies. However, studies on the effect of this or other MAGL inhibitors under hypoxia, an important factor in t...
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MDPI AG
2023-09-01
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| Online Access: | https://www.mdpi.com/2073-4409/12/19/2332 |
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| author | Felix Wittig Liza Pannenberg Rico Schwarz Sander Bekeschus Robert Ramer Burkhard Hinz |
| author_facet | Felix Wittig Liza Pannenberg Rico Schwarz Sander Bekeschus Robert Ramer Burkhard Hinz |
| author_sort | Felix Wittig |
| collection | DOAJ |
| description | JZL184, an inhibitor of monoacylglycerol lipase (MAGL) and thus of the degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG), mediates various anticancer effects in preclinical studies. However, studies on the effect of this or other MAGL inhibitors under hypoxia, an important factor in tumor biology and response to cancer therapy, have not yet been performed in cancer cells. In the present study, the impact of the conditioned media (CM) of A549 and H358 lung cancer cells incubated with JZL184 under hypoxic conditions on the angiogenic properties of human umbilical vein endothelial cells (HUVECs) was investigated. Treatment of HUVECs with CM derived from cancer cells cultured for 48 h under hypoxic conditions was associated with a substantial increase in migration and tube formation compared with unconditioned medium, which was inhibited when cancer cells were incubated with JZL184. In this process, JZL184 led to a significant increase in 2-AG levels in both cell lines. Analysis of a panel of proangiogenic factors revealed inhibition of hypoxia-induced vascular endothelial growth factor (VEGF) expression by JZL184. Antiangiogenic and VEGF-lowering effects were also demonstrated for the MAGL inhibitor MJN110. Receptor antagonist experiments suggest partial involvement of the cannabinoid receptors CB<sub>1</sub> and CB<sub>2</sub> in the antiangiogenic and VEGF-lowering effects induced by JZL184. The functional importance of VEGF for angiogenesis in the selected system is supported by observations showing inhibition of VEGF receptor 2 (VEGFR2) phosphorylation in HUVECs by CM from hypoxic cancer cells treated with JZL184 or when hypoxic cancer cell-derived CM was spiked with a neutralizing VEGF antibody. On the other hand, JZL184 did not exert a direct effect on VEGFR2 activation induced by recombinant VEGF, so there seems to be no downstream effect on already released VEGF. In conclusion, these results reveal a novel mechanism of antiangiogenic action of JZL184 under conditions of hypoxic tumor–endothelial communication. |
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| spelling | doaj.art-b7a6ef19c55d46c69e4510815a9a89f42023-11-19T14:12:16ZengMDPI AGCells2073-44092023-09-011219233210.3390/cells12192332Antiangiogenic Action of JZL184 on Endothelial Cells via Inhibition of VEGF Expression in Hypoxic Lung Cancer CellsFelix Wittig0Liza Pannenberg1Rico Schwarz2Sander Bekeschus3Robert Ramer4Burkhard Hinz5Institute of Pharmacology and Toxicology, Rostock University Medical Center, Schillingallee 70, 18057 Rostock, GermanyInstitute of Pharmacology and Toxicology, Rostock University Medical Center, Schillingallee 70, 18057 Rostock, GermanyInstitute of Pharmacology and Toxicology, Rostock University Medical Center, Schillingallee 70, 18057 Rostock, GermanyZIK <i>plasmatis</i>, Leibniz Institute for Plasma Science and Technology (INP), Felix-Hausdorff-Str. 2, 17489 Greifswald, GermanyInstitute of Pharmacology and Toxicology, Rostock University Medical Center, Schillingallee 70, 18057 Rostock, GermanyInstitute of Pharmacology and Toxicology, Rostock University Medical Center, Schillingallee 70, 18057 Rostock, GermanyJZL184, an inhibitor of monoacylglycerol lipase (MAGL) and thus of the degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG), mediates various anticancer effects in preclinical studies. However, studies on the effect of this or other MAGL inhibitors under hypoxia, an important factor in tumor biology and response to cancer therapy, have not yet been performed in cancer cells. In the present study, the impact of the conditioned media (CM) of A549 and H358 lung cancer cells incubated with JZL184 under hypoxic conditions on the angiogenic properties of human umbilical vein endothelial cells (HUVECs) was investigated. Treatment of HUVECs with CM derived from cancer cells cultured for 48 h under hypoxic conditions was associated with a substantial increase in migration and tube formation compared with unconditioned medium, which was inhibited when cancer cells were incubated with JZL184. In this process, JZL184 led to a significant increase in 2-AG levels in both cell lines. Analysis of a panel of proangiogenic factors revealed inhibition of hypoxia-induced vascular endothelial growth factor (VEGF) expression by JZL184. Antiangiogenic and VEGF-lowering effects were also demonstrated for the MAGL inhibitor MJN110. Receptor antagonist experiments suggest partial involvement of the cannabinoid receptors CB<sub>1</sub> and CB<sub>2</sub> in the antiangiogenic and VEGF-lowering effects induced by JZL184. The functional importance of VEGF for angiogenesis in the selected system is supported by observations showing inhibition of VEGF receptor 2 (VEGFR2) phosphorylation in HUVECs by CM from hypoxic cancer cells treated with JZL184 or when hypoxic cancer cell-derived CM was spiked with a neutralizing VEGF antibody. On the other hand, JZL184 did not exert a direct effect on VEGFR2 activation induced by recombinant VEGF, so there seems to be no downstream effect on already released VEGF. In conclusion, these results reveal a novel mechanism of antiangiogenic action of JZL184 under conditions of hypoxic tumor–endothelial communication.https://www.mdpi.com/2073-4409/12/19/2332angiogenesismonoacylglycerol lipaseJZL184lung cancerhypoxia |
| spellingShingle | Felix Wittig Liza Pannenberg Rico Schwarz Sander Bekeschus Robert Ramer Burkhard Hinz Antiangiogenic Action of JZL184 on Endothelial Cells via Inhibition of VEGF Expression in Hypoxic Lung Cancer Cells Cells angiogenesis monoacylglycerol lipase JZL184 lung cancer hypoxia |
| title | Antiangiogenic Action of JZL184 on Endothelial Cells via Inhibition of VEGF Expression in Hypoxic Lung Cancer Cells |
| title_full | Antiangiogenic Action of JZL184 on Endothelial Cells via Inhibition of VEGF Expression in Hypoxic Lung Cancer Cells |
| title_fullStr | Antiangiogenic Action of JZL184 on Endothelial Cells via Inhibition of VEGF Expression in Hypoxic Lung Cancer Cells |
| title_full_unstemmed | Antiangiogenic Action of JZL184 on Endothelial Cells via Inhibition of VEGF Expression in Hypoxic Lung Cancer Cells |
| title_short | Antiangiogenic Action of JZL184 on Endothelial Cells via Inhibition of VEGF Expression in Hypoxic Lung Cancer Cells |
| title_sort | antiangiogenic action of jzl184 on endothelial cells via inhibition of vegf expression in hypoxic lung cancer cells |
| topic | angiogenesis monoacylglycerol lipase JZL184 lung cancer hypoxia |
| url | https://www.mdpi.com/2073-4409/12/19/2332 |
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