iASPP-Mediated ROS Inhibition Drives 5-Fu Resistance Dependent on Nrf2 Antioxidative Signaling Pathway in Gastric Adenocarcinoma
iASPP-Mediated ROS Inhibition Drives 5-Fu Resistance Dependent on Nrf2 Antioxidative Signaling Pathway in Gastric Adenocarcinoma
复制标题
iASPP 介导的 ROS 抑制驱动胃腺癌中依赖于 Nrf2 抗氧化信号通路的 5-Fu 耐药性
DOI：
10.1007/s10620-019-06022-6
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发表时间：
2020-10-01
影响因子：
3.1
通讯作者：
Hu，Jianli
中科院分区：
文献类型：
--
作者：
Wen，Lu;Yang，Shengli;Hu，Jianli
已有报道称，p53凋亡刺激蛋白（iASPP）抑制剂与肾细胞癌中5-氟尿嘧啶（5-Fu）耐药相关。本研究揭示了iASPP-Nrf2-ROS调控5-Fu耐药的机制，这对开发胃腺癌治疗的替代治疗策略具有重要意义。方法通过TCGA RNA-seq数据、UALCAN分析和cBioPortal数据对iASPP和Nrf2进行分析。2 ',7 ' -二氯荧光素双乙酸染色测定细胞内ROS生成。特兰斯韦尔被用来评估入侵。western blot检测iASPP、Nrf2、HO-1、GSTP1的表达。结果我们发现iASPP KD导致MGC803和SCG790细胞中明显的5- fu诱导的ROS积累。伴有iASPP KD， Nrf2明显降低。iASPP诱导的ROS抑制依赖于Nrf2，由于iASPP和Nrf2均被敲低，因此与Nrf2 KD单独作用时ROS水平无明显差异。同样，iASPP KD在5-Fu处理后未能增强Nrf2 KD介导的ROS积累，这表明iASPP诱导的抗氧化作用与5-Fu抗性相关，部分依赖于Nrf2。此外，iASPP KD和Nrf2 KD联合使用对5-Fu处理后MGC803和SCG790细胞的凋亡没有任何协同作用。进一步研究发现iASPP KD或Nrf2 KD可降低HO-1和GSTP1的表达。结论sour数据表明iASPP通过清除胃腺癌组织中ROS的积累，在抑制5- fu诱导的细胞凋亡抵抗中起着至关重要的作用，并且iASPP诱导的ROS的清除依赖于Nrf2信号。
AimsInhibitor for the apoptosis-stimulating protein of p53 (iASPP) has been reported to be correlated with 5-fluorouracil (5-Fu) resistance in renal cell carcinoma. Here, we uncover mechanisms of iASPP-Nrf2-ROS regulation of 5-Fu resistance which are important for the development of alternative treatment strategies for gastric adenocarcinoma treatment.MethodsWe analyzed iASPP and Nrf2 through TCGA RNA-seq data, UALCAN analysis, and cBioPortal datasets. Intracellular ROS generation was determined by 2′,7′-dichloro-fluorescin diacetate staining. Transwell was used to evaluate the invasion. The expression of iASPP, Nrf2, HO-1, and GSTP1 was tested using western blot.ResultsWe found that iASPP KD led to an apparent 5-Fu-induced ROS accumulation in MGC803 and SCG790 cells. Accompanied by iASPP KD, Nrf2 was markedly decreased. iASPP-induced ROS inhibition relies on Nrf2, and due to both knocked down iASPP and Nrf2, the level of ROS did not show an obvious difference with Nrf2 KD solely. Similarly, iASPP KD failed to enhance the Nrf2 KD-mediated ROS accumulation after 5-Fu treatment, suggesting that iASPP-induced antioxidative effects related to 5-Fu resistance are partially dependent on Nrf2. Also, the combination of iASPP KD and Nrf2 KD did not show any synergistic effect on apoptosis after 5-Fu treatment in MGC803 and SCG790 cells. Further studies revealed that iASPP KD or Nrf2 KD could decrease the expression of HO-1 and GSTP1.ConclusionsOur data highlight that iASPP plays a crucial role in the inhibition of 5-Fu-induced apoptosis resistance by removing ROS accumulation in gastric adenocarcinoma, and that the removal of ROS induced by iASPP is Nrf2 signaling dependent.