Inhibition of lysine acetyltransferases impairs tumor angiogenesis acting on both endothelial and tumor cells.
Angiogenesis Inhibitors
/ pharmacology
Animals
Apoptosis
Cell Differentiation
Cell Movement
Cell Proliferation
Human Umbilical Vein Endothelial Cells
/ drug effects
Humans
Lung Neoplasms
/ blood supply
Lysine Acetyltransferases
/ antagonists & inhibitors
Mice
Mice, Inbred NOD
Mice, SCID
Neovascularization, Pathologic
/ drug therapy
Signal Transduction
Thiazoles
/ pharmacology
Tumor Cells, Cultured
Vascular Endothelial Growth Factor A
/ genetics
Vascular Endothelial Growth Factor Receptor-2
/ genetics
Xenograft Model Antitumor Assays
Acetylation
Endothelial cells
Lung cancer cells
Tubulin
Journal
Journal of experimental & clinical cancer research : CR
ISSN: 1756-9966
Titre abrégé: J Exp Clin Cancer Res
Pays: England
ID NLM: 8308647
Informations de publication
Date de publication:
05 Jun 2020
05 Jun 2020
Historique:
received:
27
01
2020
accepted:
25
05
2020
entrez:
6
6
2020
pubmed:
6
6
2020
medline:
5
2
2021
Statut:
epublish
Résumé
Understanding the signalling pathways involved in angiogenesis, and developing anti-angiogenic drugs are one of the major focuses on cancer research. Herein, we assessed the effect of CPTH6, a lysine acetyltransferase inhibitor and anti-tumoral compound, on angiogenesis-related properties of both endothelial and cancer cells. The in vitro effect of CPTH6 on protein acetylation and anti-angiogenic properties on endothelial and lung cancer cells was evaluated via wound healing, trans-well invasion and migration, tube formation, immunoblotting and immunofluorescence. Matrigel plug assay, zebrafish embryo and mouse xenograft models were used to evaluate in vivo anti-angiogenic effect of CPTH6. CPTH6 impaired in vitro endothelial angiogenesis-related functions, and decreased the in vivo vascularization both in mice xenografts and zebrafish embryos. Mechanistically, CPTH6 reduced α-tubulin acetylation and induced accumulation of acetylated microtubules in the perinuclear region of endothelial cells. Interestingly, CPTH6 also affected the angiogenesis-related properties of lung cancer cells, and conditioned media derived from CPTH6-treated lung cancer cells impaired endothelial cells morphogenesis. CPTH6 also modulated the VEGF/VEGFR2 pathway, and reshaped cytoskeletal organization of lung cancer cells. Finally, anti-migratory effect of CPTH6, dependent on α-tubulin acetylation, was also demonstrated by genetic approaches in lung cancer cells. Overall, this study indicates that α-tubulin acetylation could play a role in the anti-angiogenic effect of CPTH6 and, more in general, it adds information to the role of histone acetyltransferases in tumor angiogenesis, and proposes the inhibition of these enzymes as an antiangiogenic therapy of cancer.
Sections du résumé
BACKGROUND
BACKGROUND
Understanding the signalling pathways involved in angiogenesis, and developing anti-angiogenic drugs are one of the major focuses on cancer research. Herein, we assessed the effect of CPTH6, a lysine acetyltransferase inhibitor and anti-tumoral compound, on angiogenesis-related properties of both endothelial and cancer cells.
METHODS
METHODS
The in vitro effect of CPTH6 on protein acetylation and anti-angiogenic properties on endothelial and lung cancer cells was evaluated via wound healing, trans-well invasion and migration, tube formation, immunoblotting and immunofluorescence. Matrigel plug assay, zebrafish embryo and mouse xenograft models were used to evaluate in vivo anti-angiogenic effect of CPTH6.
RESULTS
RESULTS
CPTH6 impaired in vitro endothelial angiogenesis-related functions, and decreased the in vivo vascularization both in mice xenografts and zebrafish embryos. Mechanistically, CPTH6 reduced α-tubulin acetylation and induced accumulation of acetylated microtubules in the perinuclear region of endothelial cells. Interestingly, CPTH6 also affected the angiogenesis-related properties of lung cancer cells, and conditioned media derived from CPTH6-treated lung cancer cells impaired endothelial cells morphogenesis. CPTH6 also modulated the VEGF/VEGFR2 pathway, and reshaped cytoskeletal organization of lung cancer cells. Finally, anti-migratory effect of CPTH6, dependent on α-tubulin acetylation, was also demonstrated by genetic approaches in lung cancer cells.
CONCLUSION
CONCLUSIONS
Overall, this study indicates that α-tubulin acetylation could play a role in the anti-angiogenic effect of CPTH6 and, more in general, it adds information to the role of histone acetyltransferases in tumor angiogenesis, and proposes the inhibition of these enzymes as an antiangiogenic therapy of cancer.
Identifiants
pubmed: 32498717
doi: 10.1186/s13046-020-01604-z
pii: 10.1186/s13046-020-01604-z
pmc: PMC7273677
doi:
Substances chimiques
3-methylcyclopentylidene-(4-(4'-chlorophenyl)thiazol-2-yl)hydrazone
0
Angiogenesis Inhibitors
0
Thiazoles
0
VEGFA protein, human
0
Vascular Endothelial Growth Factor A
0
Lysine Acetyltransferases
EC 2.3.1.32
KDR protein, human
EC 2.7.10.1
Vascular Endothelial Growth Factor Receptor-2
EC 2.7.10.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
103Subventions
Organisme : AIRC
ID : IG18560
Organisme : Regione Lazio
ID : 15438 MITOIM
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