当前位置: X-MOL 学术Mol. Ther. Oncol. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Calcium Influx Caused by ER Stress Inducers Enhances Oncolytic Adenovirus Enadenotucirev Replication and Killing through PKCα Activation.
Molecular Therapy: Oncology ( IF 5.3 ) Pub Date : 2019-09-28 , DOI: 10.1016/j.omto.2019.09.003
William K Taverner 1 , Egon J Jacobus 1 , John Christianson 2 , Brian Champion 3 , Adrienne W Paton 4 , James C Paton 4 , Weiheng Su 1 , Ryan Cawood 5 , Len W Seymour 1 , Janet Lei-Rossmann 1
Affiliation  

Oncolytic viruses represent an emerging approach to cancer therapy. However, better understanding of their interaction with the host cancer cell and approaches to enhance their efficacy are needed. Here, we investigate the effect of chemically induced endoplasmic reticulum (ER) stress on the activity of the chimeric group B adenovirus Enadenotucirev, its closely related parental virus Ad11p, and the archetypal group C oncolytic adenovirus Ad5. We show that treatment of colorectal and ovarian cancer cell lines with thapsigargin or ionomycin caused an influx of Ca2+, leading to an upregulation in E1A transcript and protein levels. Increased E1A protein levels, in turn, increased levels of expression of the E2B viral DNA polymerase, genome replication, late viral protein expression, infectious virus particle production, and cell killing during Enadenotucirev and Ad11p, but not Ad5, infection. This effect was not due to the induction of ER stress, but rather the influx of extracellular Ca2+ and consequent increase in protein kinase C activity. These results underscore the importance of Ca2+ homeostasis during adenoviral infection, indicate a signaling pathway between protein kinase C and E1A, and raise the possibility of using Ca2+ flux-modulating agents in the manufacture and potentiation of oncolytic virotherapies.



中文翻译:


ER 应激诱导剂引起的钙流入通过 PKCα 激活增强溶瘤腺病毒 Enadenotucirev 复制和杀伤。



溶瘤病毒代表了一种新兴的癌症治疗方法。然而,需要更好地了解它们与宿主癌细胞的相互作用以及增强其功效的方法。在这里,我们研究了化学诱导的内质网(ER)应激对嵌合 B 组腺病毒 Enadenotucirev、其密切相关的亲本病毒 Ad11p 和原型 C 组溶瘤腺病毒 Ad5 活性的影响。我们发现,用毒胡萝卜素或离子霉素处理结直肠和卵巢癌细胞系会导致 Ca 2+流入,导致 E1A 转录物和蛋白质水平上调。 E1A 蛋白水平的增加反过来又增加了 E2B 病毒 DNA 聚合酶的表达水平、基因组复制、晚期病毒蛋白表达、感染性病毒颗粒的产生以及 Enadenotucirev 和 Ad11p(而非 Ad5)感染期间的细胞杀伤水平。这种效应不是由于内质网应激的诱导,而是由于细胞外Ca 2+的流入以及随之而来的蛋白激酶C 活性的增加。这些结果强调了腺病毒感染期间Ca 2+稳态的重要性,表明了蛋白激酶C 和E1A 之间的信号传导途径,并提高了在溶瘤病毒疗法的制造和增强中使用Ca 2+通量调节剂的可能性。

更新日期:2019-09-28
down
wechat
bug