Reverse effect of curcumin on CDDP-induced drug-resistance via Keap1/p62-Nrf2 signaling in A549/CDDP cell.
Reverse effect of curcumin on CDDP-induced drug-resistance via Keap1/p62-Nrf2 signaling in A549/CDDP cell.
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DOI：
10.1016/j.apjtm.2017.10.028
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发表时间：
2017-12
影响因子：
3.1
通讯作者：
Jie Shen;Ya-Juan Chen;Y. Jia;W. Zhao;Guang-Hai Chen;Ding-Feng Liu;Yun-Yu Chen;Chao Zhang;Xiao-ping Liu
中科院分区：
文献类型：
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作者：
Jie Shen;Ya-Juan Chen;Y. Jia;W. Zhao;Guang-Hai Chen;Ding-Feng Liu;Yun-Yu Chen;Chao Zhang;Xiao-ping Liu
目的观察姜黄素对顺铂耐药的影响，并通过Nrf2系统和自噬途径探讨其分子机制。方法用2μg/mL顺铂作用于A549/CDDP细胞，建立耐药细胞模型。用20μg/mLCDDP和10μM姜黄素处理A549/CDDP细胞。结果CDDP诱导A549/CDDP细胞出现耐药表型，激活A549/CDDP细胞的自噬和Nrf2信号。姜黄素联合应用可减弱CDDP诱导的自噬和Nrf2激活，逆转耐药表型。值得注意的是，姜黄素联合增强了Keap1的转录。结论CDDP可促进Nrf2途径的异常激活和自噬，导致A549/CDDP细胞耐药。姜黄素通过对Keap1转录的有效激活来减弱这一过程并对抗耐药性，Keap1转录在氧化应激诱导的Nrf2激活和自噬/凋亡开关之间的相互作用中至关重要。
ObjectiveTo assess the effect of curcumin on CDDP-induced drug resistance and explore the underlying molecular mechanism through Nrf2 system and autophagy pathway.MethodsA drug-resistant cell model was established by exposing A549/CDDP cell to 2 μg/mL CDDP. A549/CDDP cell was treated with 20 μg/mL CDDP and 10 μM curcumin. The cell viability and apoptosis level, the signals of Keap1/P62-Nrf2 and autophagy pathway were analyzed.ResultsCDDP induction promoted drug-resistant phenotype in A549/CDDP cell and activated autophagy as well as Nrf2 signals in A549/CDDP cell. Meanwhile, curcumin combination attenuated autophagy and Nrf2 activation induced by CDDP, and reversed the drug-resistant phenotype. Notably, curcumin combination augmented Keap1 transcription. Furthermore, Keap1 ablation with short hairpin RNAs hampered the efficacy of curcumin, suggesting Keap1 played a crucial role on reversal effect of curcumin.ConclusionsThe present findings demonstrate that CDDP promotes abnormal activation of Nrf2 pathway and autophagy, leading to drug resistance of A549/CDDP cell. Curcumin attenuates this process and combat drug-resistance through its potent activation on Keap1 transcription, which is essential for interplay between oxidative stress induced Nrf2 activation and autophagy/apoptosis switch.