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Abstract:

Cystic echinococcosis (CE) is a worldwide distributed helminthic zoonosis caused by Echinococcus granulosus. Benzimidazole derivatives are currently the only drugs for chemotherapeutic treatment of CE. However, their low efficacy and the adverse effects encourage the search for new therapeutic targets. We evaluated the in vitro efficacy of Bortezomib (Bz), a proteasome inhibitor, in the larval stage of the parasite. After 96 h, Bz showed potent deleterious effects at a concentration of 5 μM and 0.5 μM in protoscoleces and metacestodes, respectively (P < 0.05). After 48 h of exposure to this drug, it was triggered a mRNA overex-pression of chaperones (Eg-grp78 and Eg-calnexin) and of Eg-ire2/Eg-xbp1 (the conserved UPR pathway branch) in protoscoleces. No changes were detected in the transcriptional expression of chaperones in Bz-treated metacestodes, thus allowing ER stress to be evident and viability to highly decrease in comparison with protoscoleces. We also found that Bz treatment activated the autophagic process in both larval forms. These facts were evidenced by the increase in the amount of transcripts of the autophagy related genes (Eg-atg6, Eg-atg8, Eg-atg12, Eg-atg16) together with the increase in Eg-Atg8-II detected by western blot and by in toto immunofluorescence labeling. It was further confirmed by direct observation of autophagic structures by electronic microscopy. Finally, in order to determine the impact of autophagy induction on Echinococcus cell viability, we evaluated the efficacy of Bz in combination with rapamycin and a synergistic cytotoxic effect on protoscolex viability was observed when both drugs were used together. In conclusion, our findings demonstrated that Bz induced endoplasmic reticulum stress, autophagy and subsequent death allowing to identify unstudied parasite-host pathways that could provide a new insight for control of parasitic diseases. © 2017 Nicolao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Registro:

Documento: Artículo
Título:Bortezomib initiates endoplasmic reticulum stress, elicits autophagy and death in echinococcus granulosus larval stage
Autor:Nicolao, M.C.; Loos, J.A.; Rodrigues, C.R.; Beas, V.; Cumino, A.C.
Filiación:Laboratorio de Zoonosis Parasitarias, Departamento de Biología, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata (UNMdP), Funes, Nivel Cero, Mar del Plata, Argentina
Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina
Departamento de Química, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata (UNMdP), Funes, Nivel 2, Mar del Plata, Argentina
Hospital Privado de Comunidad, Mar del Plata, Buenos Aires, Argentina
Palabras clave:biological marker; bortezomib; chaperone; rapamycin; animal; autophagosome; autophagy; cell death; cell survival; drug effects; drug potentiation; echinococcosis; Echinococcus granulosus; endoplasmic reticulum stress; female; gene expression; genetics; larva; metabolism; mouse; parasitology; physiology; protein transport; unfolded protein response; Animals; Autophagosomes; Autophagy; Biomarkers; Bortezomib; Cell Death; Cell Survival; Drug Synergism; Echinococcosis; Echinococcus granulosus; Endoplasmic Reticulum Stress; Female; Gene Expression; Larva; Mice; Molecular Chaperones; Protein Transport; Sirolimus; Unfolded Protein Response
Año:2017
Volumen:12
Número:8
DOI: http://dx.doi.org/10.1371/journal.pone.0181528
Título revista:PLoS ONE
Título revista abreviado:PLoS ONE
ISSN:19326203
CODEN:POLNC
CAS:bortezomib, 179324-69-7, 197730-97-5; rapamycin, 53123-88-9; Biomarkers; Bortezomib; Molecular Chaperones; Sirolimus
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_19326203_v12_n8_p_Nicolao

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Citas:

---------- APA ----------
Nicolao, M.C., Loos, J.A., Rodrigues, C.R., Beas, V. & Cumino, A.C. (2017) . Bortezomib initiates endoplasmic reticulum stress, elicits autophagy and death in echinococcus granulosus larval stage. PLoS ONE, 12(8).
http://dx.doi.org/10.1371/journal.pone.0181528
---------- CHICAGO ----------
Nicolao, M.C., Loos, J.A., Rodrigues, C.R., Beas, V., Cumino, A.C. "Bortezomib initiates endoplasmic reticulum stress, elicits autophagy and death in echinococcus granulosus larval stage" . PLoS ONE 12, no. 8 (2017).
http://dx.doi.org/10.1371/journal.pone.0181528
---------- MLA ----------
Nicolao, M.C., Loos, J.A., Rodrigues, C.R., Beas, V., Cumino, A.C. "Bortezomib initiates endoplasmic reticulum stress, elicits autophagy and death in echinococcus granulosus larval stage" . PLoS ONE, vol. 12, no. 8, 2017.
http://dx.doi.org/10.1371/journal.pone.0181528
---------- VANCOUVER ----------
Nicolao, M.C., Loos, J.A., Rodrigues, C.R., Beas, V., Cumino, A.C. Bortezomib initiates endoplasmic reticulum stress, elicits autophagy and death in echinococcus granulosus larval stage. PLoS ONE. 2017;12(8).
http://dx.doi.org/10.1371/journal.pone.0181528