Inhibition of lysine acetyltransferases impairs tumor angiogenesis acting on both endothelial and tumor cells.

Abstract

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:

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:

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:

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.

• Authors: Marta Di Martile, Chiara Gabellini, Marianna Desideri, Marta Matraxia, Valentina Farini, Elisabetta Valentini, Simone Carradori, Cristiana Ercolani, Simonetta Buglioni, Daniela Secci, Massimiliano Andreazzoli, Donatella Del Bufalo, Daniela Trisciuoglio
• Journal: Journal of experimental & clinical cancer research : CR (J Exp Clin Cancer Res) Vol. 39 Issue 1 Pg. 103 (Jun 05 2020) ISSN: 1756-9966 [Electronic] England
• PMID: 32498717 (Publication Type: Journal Article)

Chemical References

• 3-methylcyclopentylidene-(4-(4'-chlorophenyl)thiazol-2-yl)hydrazone
• Angiogenesis Inhibitors
• Thiazoles
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• Lysine Acetyltransferases
• KDR protein, human
• Vascular Endothelial Growth Factor Receptor-2

Topics

• Angiogenesis Inhibitors (pharmacology)
• Animals
• Apoptosis
• Cell Differentiation
• Cell Movement
• Cell Proliferation
• Human Umbilical Vein Endothelial Cells (drug effects, metabolism)
• Humans
• Lung Neoplasms (blood supply, drug therapy, metabolism, pathology)
• Lysine Acetyltransferases (antagonists & inhibitors)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Neovascularization, Pathologic (drug therapy, metabolism, pathology)
• Signal Transduction
• Thiazoles (pharmacology)
• Tumor Cells, Cultured
• Vascular Endothelial Growth Factor A (genetics, metabolism)
• Vascular Endothelial Growth Factor Receptor-2 (genetics, metabolism)
• Xenograft Model Antitumor Assays