The Pyrazolyl-Urea Gege3 Inhibits the Activity of ANXA1 in the Angiogenesis Induced by the Pancreatic Cancer Derived EVs
The pyrazolyl-urea Gege3 molecule has shown interesting antiangiogenic effects in the tumor contest. Here, we have studied the role of this compound as interfering with endothelial cells activation in response to the paracrine effects of annexin A1 (ANXA1), known to be involved in promoting tumor pr...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-11-01
|
| Series: | Biomolecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2218-273X/11/12/1758 |
| _version_ | 1797506418813698048 |
|---|---|
| author | Raffaella Belvedere Elva Morretta Nunzia Novizio Silvana Morello Olga Bruno Chiara Brullo Antonello Petrella |
| author_facet | Raffaella Belvedere Elva Morretta Nunzia Novizio Silvana Morello Olga Bruno Chiara Brullo Antonello Petrella |
| author_sort | Raffaella Belvedere |
| collection | DOAJ |
| description | The pyrazolyl-urea Gege3 molecule has shown interesting antiangiogenic effects in the tumor contest. Here, we have studied the role of this compound as interfering with endothelial cells activation in response to the paracrine effects of annexin A1 (ANXA1), known to be involved in promoting tumor progression. ANXA1 has been analyzed in the extracellular environment once secreted through microvesicles (EVs) by pancreatic cancer (PC) cells. Particularly, Gege3 has been able to notably prevent the effects of Ac2-26, the ANXA1 mimetic peptide, and of PC-derived EVs on endothelial cells motility, angiogenesis, and calcium release. Furthermore, this compound also inhibited the translocation of ANXA1 to the plasma membrane, otherwise induced by the same ANXA1-dependent extracellular stimuli. Moreover, these effects have been mediated by the indirect inhibition of protein kinase Cα (PKCα), which generally promotes the phosphorylation of ANXA1 on serine 27. Indeed, by the subtraction of intracellular calcium levels, the pathway triggered by PKCα underwent a strong inhibition leading to the following impediment to the ANXA1 localization at the plasma membrane, as revealed by confocal and cytofluorimetry analysis. Thus, Gege3 appeared an attractive molecule able to prevent the paracrine effects of PC cells deriving ANXA1 in the tumor microenvironment. |
| first_indexed | 2024-03-10T04:33:22Z |
| format | Article |
| id | doaj.art-076a6f4bbdb045e3ba8a0ef36b1de5ba |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T04:33:22Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-076a6f4bbdb045e3ba8a0ef36b1de5ba2023-11-23T03:58:42ZengMDPI AGBiomolecules2218-273X2021-11-011112175810.3390/biom11121758The Pyrazolyl-Urea Gege3 Inhibits the Activity of ANXA1 in the Angiogenesis Induced by the Pancreatic Cancer Derived EVsRaffaella Belvedere0Elva Morretta1Nunzia Novizio2Silvana Morello3Olga Bruno4Chiara Brullo5Antonello Petrella6Department of Pharmacy, University of Salerno, Viale Giovanni Paolo II, Fisciano, 84084 Salerno, ItalyDepartment of Pharmacy, University of Salerno, Viale Giovanni Paolo II, Fisciano, 84084 Salerno, ItalyDepartment of Pharmacy, University of Salerno, Viale Giovanni Paolo II, Fisciano, 84084 Salerno, ItalyDepartment of Pharmacy, University of Salerno, Viale Giovanni Paolo II, Fisciano, 84084 Salerno, ItalyDepartment of Pharmacy, University of Genova, Viale Benedetto XV 3, 16132 Genova, ItalyDepartment of Pharmacy, University of Genova, Viale Benedetto XV 3, 16132 Genova, ItalyDepartment of Pharmacy, University of Salerno, Viale Giovanni Paolo II, Fisciano, 84084 Salerno, ItalyThe pyrazolyl-urea Gege3 molecule has shown interesting antiangiogenic effects in the tumor contest. Here, we have studied the role of this compound as interfering with endothelial cells activation in response to the paracrine effects of annexin A1 (ANXA1), known to be involved in promoting tumor progression. ANXA1 has been analyzed in the extracellular environment once secreted through microvesicles (EVs) by pancreatic cancer (PC) cells. Particularly, Gege3 has been able to notably prevent the effects of Ac2-26, the ANXA1 mimetic peptide, and of PC-derived EVs on endothelial cells motility, angiogenesis, and calcium release. Furthermore, this compound also inhibited the translocation of ANXA1 to the plasma membrane, otherwise induced by the same ANXA1-dependent extracellular stimuli. Moreover, these effects have been mediated by the indirect inhibition of protein kinase Cα (PKCα), which generally promotes the phosphorylation of ANXA1 on serine 27. Indeed, by the subtraction of intracellular calcium levels, the pathway triggered by PKCα underwent a strong inhibition leading to the following impediment to the ANXA1 localization at the plasma membrane, as revealed by confocal and cytofluorimetry analysis. Thus, Gege3 appeared an attractive molecule able to prevent the paracrine effects of PC cells deriving ANXA1 in the tumor microenvironment.https://www.mdpi.com/2218-273X/11/12/1758Gege3annexin A1extracellular vesiclesangiogenesisPKCα inhibitioncalcium mobilization |
| spellingShingle | Raffaella Belvedere Elva Morretta Nunzia Novizio Silvana Morello Olga Bruno Chiara Brullo Antonello Petrella The Pyrazolyl-Urea Gege3 Inhibits the Activity of ANXA1 in the Angiogenesis Induced by the Pancreatic Cancer Derived EVs Biomolecules Gege3 annexin A1 extracellular vesicles angiogenesis PKCα inhibition calcium mobilization |
| title | The Pyrazolyl-Urea Gege3 Inhibits the Activity of ANXA1 in the Angiogenesis Induced by the Pancreatic Cancer Derived EVs |
| title_full | The Pyrazolyl-Urea Gege3 Inhibits the Activity of ANXA1 in the Angiogenesis Induced by the Pancreatic Cancer Derived EVs |
| title_fullStr | The Pyrazolyl-Urea Gege3 Inhibits the Activity of ANXA1 in the Angiogenesis Induced by the Pancreatic Cancer Derived EVs |
| title_full_unstemmed | The Pyrazolyl-Urea Gege3 Inhibits the Activity of ANXA1 in the Angiogenesis Induced by the Pancreatic Cancer Derived EVs |
| title_short | The Pyrazolyl-Urea Gege3 Inhibits the Activity of ANXA1 in the Angiogenesis Induced by the Pancreatic Cancer Derived EVs |
| title_sort | pyrazolyl urea gege3 inhibits the activity of anxa1 in the angiogenesis induced by the pancreatic cancer derived evs |
| topic | Gege3 annexin A1 extracellular vesicles angiogenesis PKCα inhibition calcium mobilization |
| url | https://www.mdpi.com/2218-273X/11/12/1758 |
| work_keys_str_mv | AT raffaellabelvedere thepyrazolylureagege3inhibitstheactivityofanxa1intheangiogenesisinducedbythepancreaticcancerderivedevs AT elvamorretta thepyrazolylureagege3inhibitstheactivityofanxa1intheangiogenesisinducedbythepancreaticcancerderivedevs AT nunzianovizio thepyrazolylureagege3inhibitstheactivityofanxa1intheangiogenesisinducedbythepancreaticcancerderivedevs AT silvanamorello thepyrazolylureagege3inhibitstheactivityofanxa1intheangiogenesisinducedbythepancreaticcancerderivedevs AT olgabruno thepyrazolylureagege3inhibitstheactivityofanxa1intheangiogenesisinducedbythepancreaticcancerderivedevs AT chiarabrullo thepyrazolylureagege3inhibitstheactivityofanxa1intheangiogenesisinducedbythepancreaticcancerderivedevs AT antonellopetrella thepyrazolylureagege3inhibitstheactivityofanxa1intheangiogenesisinducedbythepancreaticcancerderivedevs AT raffaellabelvedere pyrazolylureagege3inhibitstheactivityofanxa1intheangiogenesisinducedbythepancreaticcancerderivedevs AT elvamorretta pyrazolylureagege3inhibitstheactivityofanxa1intheangiogenesisinducedbythepancreaticcancerderivedevs AT nunzianovizio pyrazolylureagege3inhibitstheactivityofanxa1intheangiogenesisinducedbythepancreaticcancerderivedevs AT silvanamorello pyrazolylureagege3inhibitstheactivityofanxa1intheangiogenesisinducedbythepancreaticcancerderivedevs AT olgabruno pyrazolylureagege3inhibitstheactivityofanxa1intheangiogenesisinducedbythepancreaticcancerderivedevs AT chiarabrullo pyrazolylureagege3inhibitstheactivityofanxa1intheangiogenesisinducedbythepancreaticcancerderivedevs AT antonellopetrella pyrazolylureagege3inhibitstheactivityofanxa1intheangiogenesisinducedbythepancreaticcancerderivedevs |