Inhibition of the unfolded protein response by ricin a-chain enhances its cytotoxicity in mammalian cells.
Inhibition of the unfolded protein response by ricin a-chain enhances its cytotoxicity in mammalian cells.
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DOI：
10.3390/toxins3050453
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发表时间：
2011-05
期刊：
影响因子：
4.2
通讯作者：
Cohick WS
中科院分区：
文献类型：
--
作者：
Wang CT;Jetzt AE;Cheng JS;Cohick WS
蓖麻毒素是一种剧毒的II型核糖体失活蛋白，有可能作为生化武器和免疫毒素的有毒成分。未折叠蛋白反应(UPR)是一种帮助细胞从内质网(ER)应激中恢复的生存反应。未能从内质网应激中恢复会导致细胞凋亡。在酵母中，蓖麻毒素的酶成分蓖麻毒素-A链(RTA)抑制UPR。我们的目标是确定RTA是否抑制两种上皮细胞系中的UPR，以及这是否影响RTA的细胞毒性。RTA本身并不能诱发UPR。然而，RTA既抑制了肌醇需要酶1(IRE1)的磷酸化，也抑制了UPR诱导剂衣霉素(TM)对X-box结合蛋白1mRNA的剪接。二硫苏糖醇(DTT)激活真核细胞翻译起始因子2α(eIF2α)的能力也被抑制。RTA与TM或DTT联合处理对单个细胞系蛋白质合成的抑制作用比单独使用任何一种药物更明显，而caspase的裂解作用在两种细胞系中均得到增强。这些数据表明，当UPR被抑制时，RTA具有更强的细胞毒性。这种抑制UPR的能力可能会增强RTA作为实体瘤治疗性免疫毒素的潜力。
Ricin is a highly toxic type II ribosome-inactivating protein that has potential as a biochemical weapon and as the toxic component of immunotoxins. The unfolded protein response (UPR) is a survival response that helps cells to recover from endoplasmic reticulum (ER) stress. Failure to recover from ER stress leads to apoptosis. In yeast, ricin-A-chain (RTA), the enzymatic component of ricin, inhibits UPR. Our goals were to determine if RTA inhibits UPR in two epithelial cell lines and if this affects RTA cytotoxicity. RTA alone did not induce UPR. However, RTA inhibited both phosphorylation of inositol-requiring enzyme 1 (IRE1) and splicing of X-box binding protein1 mRNA by the UPR-inducing agent tunicamycin (Tm). The ability of dithiothreitol (DTT) to activate eukaryotic translation initiation factor 2 alpha (eIF2α), a component of the PERK pathway, was also inhibited by RTA. Treatment with RTA in combination with Tm or DTT inhibited protein synthesis more than either agent did alone in one cell line, while caspase cleavage was enhanced by the treatment combination in both cell lines. These data indicate that RTA is more cytotoxic when UPR is inhibited. This ability to inhibit UPR may enhance the potential of RTA as a therapeutic immunotoxin in solid tumors.
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DOI：
10.1016/j.biocel.2009.08.007
发表时间：
2009-12-01
影响因子：
4
作者：
Jetzt, Amanda E.;Cheng, Ju-Shun;Cohick, Wendie S.
通讯作者：
Cohick, Wendie S.
影响因子：
3.1
作者：
Li, Xiao-Ping;Baricevic, Marianne;Tumer, Nigun E.
通讯作者：
Tumer, Nigun E.
影响因子：
16
作者：
Harding, HP;Zhang, YH;Ron, D
通讯作者：
Ron, D
影响因子：
3.3
作者：
Li, Shuyu;Spooner, Robert A.;Roberts, Lynne M.
通讯作者：
Roberts, Lynne M.
影响因子：
64.8
作者：
Calfon, M;Zeng, HQ;Ron, D
通讯作者：
Ron, D