Chrysin enhances sensitivity of BEL-7402/ADM cells to doxorubicin by suppressing PI3K/Akt/Nrf2 and ERK/Nrf2 pathway
Chrysin enhances sensitivity of BEL-7402/ADM cells to doxorubicin by suppressing PI3K/Akt/Nrf2 and ERK/Nrf2 pathway
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DOI：
10.1016/j.cbi.2013.08.008
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发表时间：
2013-10-25
影响因子：
5.1
通讯作者：
Chen, Hui
中科院分区：
文献类型：
--
作者：
Gao, Ai-Mei;Ke, Zun-Ping;Chen, Hui
核因子-E2相关因子2(Nrf2)是一种重要的细胞保护性转录因子，在抗氧化和解毒过程中起着关键作用。最近的研究报道，在许多类型的癌细胞中，化疗耐药的发生与Nrf2介导的信号通路的结构性激活有关。在此，我们研究了Nrf2是否与耐阿霉素的BEL-7402(BEL-7402/ADM)细胞耐药有关，以及白杨素是否能逆转BEL-7402/ADM细胞的耐药性。我们发现BEL7402/ADM细胞中Nrf2及其靶蛋白的表达水平明显高于BEL-7402细胞。同样，NR12 siRNA显著降低BEL-74021ADM细胞内Nrf2蛋白水平，部分逆转ADM耐药性。白杨素是一种有效的Nrf2抑制剂，可使BEL-7402/ADM细胞对ADM增敏，并增加细胞内ADM浓度。机制上，白杨素通过下调PI3K-Akt和ERK信号通路，显著降低Nrf2在mRNA和蛋白水平的表达。因此，Nrf2下游基因HO-1、AKR1B10和MRP5的表达减少，并抑制了Nrf2依赖的化疗耐药。综上所述，这些结果表明Nrf2的激活与BEL-7402/ADM细胞的耐药性有关，白杨素可能是一种有效的佐剂增敏剂，通过下调Nrf2信号通路来降低抗癌药物的耐药性。(C)2013爱思唯尔爱尔兰有限公司。保留所有权利。
Nuclear factor-E2-related factor 2 (Nrf2) is an important cytoprotective transcription factor which plays a key role in antioxidant and detoxification processes. Recent studies have reported that development of chemoresistance is associated with the constitutive activation of the Nrf2-mediated signaling pathway in many types of cancer cells. Here, we investigated whether Nrf2 was associated with drug resistant in doxorubicin resistant BEL-7402 (BEL-7402/ADM) cells, and if chrysin could reverse drug resistance in BEL-7402/ADM cells. We found that remarkable higher level of Nrf2 and its target proteins in BEL7402/ADM cells compared to BEL-7402 cells. Similarly, intracellular Nrf2 protein level was significantly decreased and ADM resistance was partially reversed by Nr12 siRNA in BEL-74021ADM cells. chrysin is a potent Nrf2 inhibitor which sensitizes BEL-7402/ADM cells to ADM and increases intracellular concentration of ADM. Mechanistically, chrysin significantly reduced Nrf2 expression at both the mRNA and protein levels through down-regulating PI3K-Akt and ERK pathway. Consequently, expression of Nrf2downstream genes HO-1, AKR1B10, and MRP5 were reduced and the Nrf2-dependent chemoresistance was suppressed. In conclusion, these results clearly indicate that activation of Nrf2 is associated with drug resistance in BEL-7402/ADM cells and chrysin may be an effective adjuvant sensitizer to reduce anticancer drug resistance by down-regulating Nrf2 signaling pathway. (C) 2013 Elsevier Ireland Ltd. All rights reserved.