MVL-PLA2, a snake venom phospholipase A2, inhibits angiogenesis through an increase in microtubule dynamics and disorganization of focal adhesions.
Integrins are essential protagonists of the complex multi-step process of angiogenesis that has now become a major target for the development of anticancer therapies. We recently reported and characterized that MVL-PLA2, a novel phospholipase A2 from Macrovipera lebetina venom, exhibited anti-integrin activity. In this study, we show that MVL-PLA2 also displays potent anti-angiogenic properties. This phospholipase A2 inhibited adhesion and migration of human microvascular-endothelial cells (HMEC-1) in a dose-dependent manner without being cytotoxic. Using Matrigel and chick chorioallantoic membrane assays, we demonstrated that MVL-PLA2, as well as its catalytically inactivated form, significantly inhibited angiogenesis both in vitro and in vivo. We have also found that the actin cytoskeleton and the distribution of alphav beta3 integrin, a critical regulator of angiogenesis and a major component of focal adhesions, were disturbed after MVL-PLA2 treatment. In order to further investigate the mechanism of action of this protein on endothelial cells, we analyzed the dynamic instability behavior of microtubules in living endothelial cells. Interestingly, we showed that MVL-PLA2 significantly increased microtubule dynamicity in HMEC-1 cells by 40%. We propose that the enhancement of microtubule dynamics may explain the alterations in the formation of focal adhesions, leading to inhibition of cell adhesion and migration.
Bazaa
Amine
A
Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, Tunis, Tunisia.
Pasquier
Eddy
E
Defilles
Céline
C
Limam
Ines
I
Kessentini-Zouari
Raoudha
R
Kallech-Ziri
Olfa
O
El Battari
Assou
A
Braguer
Diane
D
El Ayeb
Mohamed
M
Marrakchi
Naziha
N
Luis
José
J
D020533:Angiogenesis Inhibitors; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000166:cytology; D022001:Focal Adhesions / Q000378:metabolism*; D006801:Humans; D008870:Microtubules / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D054467:Phospholipases A2 / Q000494:pharmacology*; D012910:Snake Venoms / Q000494:pharmacology
D020533:Angiogenesis Inhibitors; D012910:Snake Venoms; D054467:Phospholipases A2
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