PSMD4 is a novel therapeutic target in chemoresistant colorectal cancer activated by cytoplasmic localization of Nrf2.
PSMD4 is a novel therapeutic target in chemoresistant colorectal cancer activated by cytoplasmic localization of Nrf2.
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PSMD4是通过NRF2的细胞质定位激活的化学抗性结直肠癌的新型治疗靶标。
DOI：
10.18632/oncotarget.25254
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发表时间：
2018-05-29
期刊：
影响因子：
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通讯作者：
Lee H
中科院分区：
文献类型：
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作者：
Cheng YM;Lin PL;Wu DW;Wang L;Huang CC;Lee H
核Nrf 2（nNrf 2）与抗氧化反应元件的结合可能促进结直肠癌的化疗耐药性。然而，Nrf 2在结肠癌细胞中的细胞质和细胞核之间的穿梭揭示了Nrf 2（cNrf 2）的细胞质定位可能在化学抗性中起特定作用的可能性。使用MTT测定法将核定位序列（NLS）-野生型或NLS-突变的Nrf 2表达载体转染到稳定的shNrf 2 HCT 116克隆中，以检查cNrf 2诱导的化学抗性是否可能大于nNrf 2。使用不同的特异性抑制剂和靶向基因的小发夹（sh）RNA来验证cNrf 2在化学抗性中的机制作用，并通过动物模型进一步证实。统计分析cNrf 2与结直肠癌患者化疗反应的相关性。MTT法显示cNrf 2可能比nNrf 2在增加HCT 116细胞对5-氟尿嘧啶（5-FU）和奥沙利铂的耐药性方面发挥更重要的作用。从机制上讲，cNrf 2诱导的PSMD 4表达通过NF-κB/AKT/β-catenin/ZEB 1级联反应负责NLS突变的Nrf 2转染的shNrf 2 HCT 116克隆中的化学抗性。NLS突变的Nrf 2转染的shNrf 2 HCT 116克隆诱导的肿瘤负荷通过5-FU联合卡非佐米治疗完全抑制。在cNrf 2、PSMD 4阳性、p-p65阳性和核β-连环蛋白肿瘤的结直肠癌患者中，与其对应患者相比，观察到不良化疗反应的发生率更高。cNrf 2在大肠癌耐药中可能起着比nNrf 2更重要的作用。PSMD 4激活NF-κB/AKT/β-catenin/ZEB 1级联反应可能是cNrf 2介导的化疗耐药性的原因。CNrf 2可能在5-FU和奥沙利铂耐药中发挥比nNrf 2更重要的作用。在患者中的这一观察结果似乎支持细胞和动物模型的发现，并表明PSMD 4可能是通过NF-κB/AKT/β-连环蛋白/ZEB 1级联介导的cNrf 2介导的化学抗性的原因。
Nuclear Nrf2 (nNrf2) binding to the antioxidant response element may promote chemoresistance in colorectal cancer. However, the shuttling of Nrf2 between cytoplasm and nucleus in colon cancer cells has revealed the possibility that cytoplasmic location of Nrf2 (cNrf2) may play a specific role in chemoresistance. Transfection of a nuclear location sequence (NLS)-wild-type or NLS-mutated Nrf2 expression vector into a stable shNrf2 HCT116 clone using the MTT assay to examine whether chemoresistance induced by cNrf2 may be greater than nNrf2. Different specific inhibitors and small hairpin (sh)RNAs of targeting genes were used to verify the mechanistic action of cNrf2 in chemoresistance and further confirmed by an animal model. The association of cNrf2 with chemotherapeutic response in patients with colorectal cancer was statistically analyzed. The MTT assay indicated that cNrf2 may play a more important role than nNrf2 in conferring 5-fluorouracil (5-FU) and oxaliplatin resistance in HCT116 cells. Mechanistically, cNrf2-induced PSMD4 expression was responsible for chemoresistance in the NLS-mutated Nrf2-tranfected shNrf2HCT116 clone via the NF-κB/AKT/β-catenin/ZEB1 cascades. The tumor burden induced by the NLS-mutated Nrf2-transfected shNrf2HCT116 clone was completely suppressed by treatment with 5-FU in combination with carfilzomib. A higher prevalence of unfavorable chemotherapeutic response in colorectal cancer patients with cNrf2, PSMD4-positive, p-p65-positive, and nuclear β-catenin tumors was observed when compared to their counterparts. cNrf2 may play a more important role than nNrf2 in the chemoresistance of colorectal cancer. Activation of the NF-κB/AKT/β-catenin/ZEB1 cascade by PSMD4 may be responsible for cNrf2-mediated chemoresistance. CNrf2 may play a more important role than nNrf2 in conferring 5-FU and oxaliplatin resistance. This observation in patients seemed to support the findings of the cell and animal models and suggested that PSMD4 may be responsible cNrf2-mediated chemoresistance via the NF-κB/AKT/β-catenin /ZEB1 cascades.