Human breast cancer cell death induced by BnSP-6, a Lys-49 PLA2 homologue from Bothrops pauloensis venom

Azevedo, Fernanda Van Petten de Vasconcelos; Lopes, Daiana Silva; Gimenes, Sarah Natalie Cirilo; Achê, David Collares; Vecchi, Lara; Alves, Patrícia Terra; Guimarães, Denise de Oliveira; Rodrigues, Renata Santos; Goulart, Luiz Ricardo; Ávila, Veridiana de Melo Rodrigues; Yoneyama, Kelly Aparecida Geraldo

doi:10.1016/j.ijbiomac.2015.10.080

Cited by 43 publications

(33 citation statements)

References 57 publications

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“…Moreover, snake‐venom‐mediated apoptosis is suggested to be not exclusively triggered by SV‐LAAOs as other components of snake venoms, namely PLA 2 s and SVMPs may also promote apoptotic cell death (Azevedo et al, ; Bustillo, Van de Velde, Matzner Perfumo, Gay, & Leiva, ; Guimaraes et al, ). BnSP‐6, a Lys 49 PLA 2 (Azevedo et al, ) and bothropoidin, a metalloproteinase (Guimaraes et al, ) isolated from Bothrops pauloensis snake‐venom‐induced apoptosis in MDA‐MB‐231 human breast cancer cells, and baltergin, a PIII metalloprotease isolated from Bothrops alternatus snake‐venom‐stimulated apoptotic cell death in C2C12 mouse muscle cells (Bustillo et al, ). Thus, one can conclude that also PLA 2 s and SVMPs found in higher concentrations in Venom 3 and Venom 4 compared with Venom 1 and Venom 2 may also account for a weak proapoptotic activity of Venom 3 and Venom 4 (this study).…”

Section: Discussionmentioning

confidence: 99%

Snake venoms promote stress‐induced senescence in human fibroblasts

Lewińska

Bocian

Petrílla

et al. 2018

Journal Cellular Physiology

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Snake venoms are widely studied in terms of their systemic toxicity and proteolytic, hemotoxic, neurotoxic, and cytotoxic activities. However, little is known about snakevenom-mediated effects when used at low, noncytotoxic concentrations. In the current study, two human fibroblast cell lines of different origin, namely WI-38 fetal lung fibroblasts and BJ foreskin fibroblasts were used to investigate snake-venominduced adaptive response at a relatively noncytotoxic concentration (0.01 µg/ml).The venoms of Indochinese spitting cobra (Naja siamensis), western green mamba (Dendroaspis viridis), forest cobra (Naja melanoleuca), and southern copperhead (Agkistrodon contortrix) were considered. Snake venoms promoted FOXO3a-mediated oxidative stress response and to a lesser extent DNA damage response, which lead to changes in cell cycle regulators both at messenger RNA and protein levels, limited cell proliferation and migration, and induced cellular senescence. Taken together, we have shown for the first time that selected snake venoms may also exert adverse effects when used at relatively noncytotoxic concentrations. K E Y W O R D Scellular senescence, fibroblasts, oxidative stress and DNA damage response (DDR), proliferation, snake venoms

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Section: Discussionmentioning

confidence: 99%

Snake venoms promote stress‐induced senescence in human fibroblasts

Lewińska

Bocian

Petrílla

et al. 2018

Journal Cellular Physiology

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“…Second, the interaction of Mt-II with NCL may explain pharmacological properties of snake myotoxins. The preferential activity of these toxins against cancer cells (6,39,40) can be correlated to the fact that NCL is more abundant on the surface of these cells (16,41,42). Moreover, some snake PLA 2 s have been reported to have antiviral activity (43,44) and accordingly NCL is involved in internalization of many viruses (16,17).…”

Section: Discussionmentioning

confidence: 99%

Nucleolin internalizesBothrops asperLys49 phospholipase A₂forming cell surface amyloid-like assemblies

Massimino

Simonato

Spolaore

et al. 2017

Preprint

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Phospholipases A 2 (PLA 2 s) are a major component of snake venoms. Some of them cause severe muscle necrosis through a still unknown mechanism. Phospholipid hydrolysis is a possible explanation of their toxic action, but catalytic and toxic properties of PLA 2 s are not directly connected. In addition, viperid venoms contain PLA 2 -like proteins, which are very toxic even if they lack catalytic activity due to a critical mutation in position 49.Nucleolin, a main component of the nucleolus, is a disordered protein involved in many protein assembly and phase separation phenomena. In some circumstances nucleolin is exposed on the cell surface from where it is involved in the internalization of many ligands.In this work we demonstrate that Bothrops asper myotoxin II (Mt-II), a Lys49 PLA 2 -like toxin, interacts with, and is internalized in cells by nucleolin. The internalization process is functional to the toxicity of the protein, as both an antibody and an aptamer specific for nucleolin protect cells from intoxication. We identified central RRM and the C-terminal R/F-GG domain of nucleolin as the regions involved in the interaction with Mt-II.Finally we observed that Mt-II forms, on the cell surface, amyloid-like assemblies that colocalize with nucleolin and that can be involved in the activation of the internalization process. The presence, in the three dimensional structure of Mt-II and related PLA 2 homologues, of four exposed loops enriched in prion-like amino acid sequences reinforces this hypothesis.Phospholipases A 2 | Lys49 myotoxins | nucleolin | amyloid-like | molecular assemblies SIGNIFICANCEThe main finding of this work, the role of nucleolin as Bothrops asper Mt-II receptor, is a remarkable step forward in understanding the mechanism of action of cytotoxic PLA 2 s. It may suggest new strategies for anti-venom therapies and explain the anti-tumoral and anti-viral pharmacological action of snake PLA 2 s, since nucleolin is a receptor for many growth factors and virus.The proposed internalization mechanism, via formation of molecular assemblies among Mt-II amyloid-like structures and other proteins, including nucleolin, can be of general validity. Cell surface molecular assemblies could be points of selection and concentration not only of snake, but also of mammalian secreted PLA 2 s,

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“…Nos últimos anos, novas classes de antibióticos, incluindo proteínas de animais e peptídeos antimicrobianos, têm sido investigados como uma alternativa para vários problemas, como a resistência microbiana (MATSUZAKI et al, 1997). Como exemplo de possíveis aplicações, o veneno das serpentes apresenta atividades como: antibacteriano (RODRIGUES et al, 2009;SILVEIRA et al, 2013;PERUMALSAMMY et al, 2014); antitumoral (RODRIGUES et al, 2007;BURIN et al, 2013;AZEVEDO et al, 2016); antiviral (MULLER et al, 2014);…”

Section: Conclusãounclassified

“…).Para purificar Lys-49, uma fosfolipase presente no veneno de B. pauloensis, foram utilizados dois passos cromatográficos onde a molécula alvo tinha aproximadamente 14 kDa, necessitando 47% de acetonitrila para a sua eluição(AZEVEDO et al, 2016). Segundo Moura e colaboradores (2014), foi possível eluir uma fosfolipase com 47% de acetonitrila, a Asp49, que foi purificada da toxina de B. mattogrossensis.Aproximadamente 80% de acetonitrila foi utilizada para eluir uma fosfolipase do veneno de B. jararacussu, uma porcentagem maior se comparada com as outras citadas(MOURA et al, 2014).…”

unclassified

Estudo da herpetofauna brasileira

Oldiges¹

2018

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Human breast cancer cell death induced by BnSP-6, a Lys-49 PLA2 homologue from Bothrops pauloensis venom

Cited by 43 publications

References 57 publications

Snake venoms promote stress‐induced senescence in human fibroblasts

Snake venoms promote stress‐induced senescence in human fibroblasts

Nucleolin internalizesBothrops asperLys49 phospholipase A₂forming cell surface amyloid-like assemblies

Estudo da herpetofauna brasileira

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Human breast cancer cell death induced by BnSP-6, a Lys-49 PLA2 homologue from Bothrops pauloensis venom

Cited by 43 publications

References 57 publications

Snake venoms promote stress‐induced senescence in human fibroblasts

Snake venoms promote stress‐induced senescence in human fibroblasts

Nucleolin internalizesBothrops asperLys49 phospholipase A2forming cell surface amyloid-like assemblies

Estudo da herpetofauna brasileira

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Nucleolin internalizesBothrops asperLys49 phospholipase A₂forming cell surface amyloid-like assemblies