Department of Animal Sciences, Rutgers, The State University of NJ, School of Environmental and Biological Sciences, New Brunswick, NJ 08901, USA.
Toxins (Basel). 2011 May;3(5):453-68. doi: 10.3390/toxins3050453. Epub 2011 May 10.
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.
蓖麻毒素是一种具有潜在生物武器和免疫毒素毒性成分的 II 型核糖体失活蛋白。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。如果不能从 ER 应激中恢复，就会导致细胞凋亡。在酵母中，蓖麻毒素 A 链 (RTA)，即蓖麻毒素的酶成分，可抑制 UPR。我们的目标是确定 RTA 是否在两种上皮细胞系中抑制 UPR，以及这是否会影响 RTA 的细胞毒性。单独的 RTA 本身不会诱导 UPR。然而，RTA 抑制了 UPR 诱导剂衣霉素 (Tm) 诱导的肌醇需求酶 1 (IRE1) 磷酸化和 X 盒结合蛋白 1 mRNA 的剪接。二硫苏糖醇 (DTT) 激活真核翻译起始因子 2 阿尔法 (eIF2α) 的能力，PERK 途径的一个组成部分，也被 RTA 抑制。在一种细胞系中，RTA 与 Tm 或 DTT 联合处理抑制蛋白合成的能力强于单独使用任何一种药物，而在两种细胞系中，caspase 切割都被处理组合增强。这些数据表明，当 UPR 被抑制时，RTA 的细胞毒性更强。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。
