Bortezomib initiates endoplasmic reticulum stress, elicits autophagy and death in Echinococcus granulosus larval stage.
Bortezomib initiates endoplasmic reticulum stress, elicits autophagy and death in Echinococcus granulosus larval stage.
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DOI：
10.1371/journal.pone.0181528
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Cumino AC
中科院分区：
文献类型：
--
作者：
Nicolao MC;Loos JA;Rodriguez Rodrigues C;Beas V;Cumino AC
囊状棘球蚴病是由细粒棘球蚴引起的一种世界性分布的人畜共患蠕虫病。苯并咪唑衍生物是目前唯一用于CE化疗的药物。然而，它们的低疗效和副作用促使人们寻找新的治疗靶点。我们评估了蛋白酶体抑制剂硼替佐米（Bz）在寄生虫幼虫期的体外疗效。Bz浓度为5 μM和0.5 μM时，96 h后对原绦虫和后绦虫的毒性作用显著（P < 0.05）。暴露于该药物48 h后，在原核细胞中触发了伴侣蛋白（Eg-grp 78和Eg-calnexin）和Eg-ire 2/Eg-xbp 1（保守的UPR途径分支）的mRNA过表达。在Bz处理的后囊蚴中没有检测到伴侣蛋白的转录表达的变化，因此与原囊蚴相比，ER应激是明显的，并且活力高度降低。我们还发现，Bz治疗激活自噬过程中的两种幼虫形式。这些事实通过自噬相关基因（Eg-atg 6、Eg-atg 8、Eg-atg 12、Eg-atg 16）的转录物的量的增加以及通过蛋白质印迹和整体免疫荧光标记检测到的Eg-Atg 8-II的增加来证明。通过电子显微镜直接观察自噬结构进一步证实。最后，为了确定自噬诱导对棘球蚴细胞活力的影响，我们评估了Bz与雷帕霉素组合的功效，并且当两种药物一起使用时，观察到对原头节活力的协同细胞毒性作用。总之，我们的研究结果表明，Bz诱导内质网应激，自噬和随后的死亡，允许确定未研究的寄生虫-宿主途径，可以为控制寄生虫病提供新的见解。
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 overexpression 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.
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影响因子：
10.6
作者：
Kaushik, S.;Cuervo, A. M.
通讯作者：
Cuervo, A. M.
影响因子：
3.6
作者：
Cabezon, Carolina;Cabrera, Gonzalo;Galanti, Norbel
通讯作者：
Galanti, Norbel
影响因子：
4.9
作者：
Celeste Nicolao, Maria;Celina Elissondo, Maria;Cumino, Andrea C.
通讯作者：
Cumino, Andrea C.
影响因子：
4.8
作者：
Kisselev, AF;Callard, A;Goldberg, AL
通讯作者：
Goldberg, AL
DOI：
10.3324/haematol.2011.058677
发表时间：
2012-09-01
期刊：
HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
影响因子：
--
作者：
Caballero-Velazquez, Teresa;Sanchez-Abarca, Luis Ignacio;Perez-Simon, Jose A.
通讯作者：
Perez-Simon, Jose A.