Endoplasmic reticulum stress-induced resistance to doxorubicin is reversed by paeonol treatment in human hepatocellular carcinoma cells.
Endoplasmic reticulum stress-induced resistance to doxorubicin is reversed by paeonol treatment in human hepatocellular carcinoma cells.
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在人肝细胞癌细胞中，丹皮酚处理可逆转内质网应激诱导的多柔比星耐药性。
DOI：
10.1371/journal.pone.0062627
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Wei W
中科院分区：
文献类型：
--
作者：
Fan L;Song B;Sun G;Ma T;Zhong F;Wei W
内质网应激（ER应激）在实体瘤中普遍被激活，导致肿瘤细胞抗凋亡和耐药。丹皮酚（Pae，2-羟基-4-甲氧基苯乙酮）是从牡丹皮的根中提取的天然产物。尽管 Pae 在各种细胞系和动物模型中表现出抗肿瘤活性并提高化疗药物的疗效，但有关 Pae 对内质网应激诱导的肝细胞癌 (HCC) 化疗药物耐药性影响的研究知之甚少。在这项研究中，我们研究了人肝细胞癌细胞对阿霉素耐药过程中内质网（ER）应激反应的影响。在添加阿霉素之前用内质网应激诱导剂衣霉素 (TM) 治疗可降低阿霉素诱导的细胞凋亡率。有趣的是，衣霉素和 Pae 联合预处理显着增加了阿霉素诱导的细胞凋亡。此外，ER应激的诱导导致HepG2细胞中COX-2表达增加，同时Akt失活和促凋亡转录因子CHOP (GADD153)上调。这些基因表达和 Akt 激活的细胞变化可能是经历 ER 应激的肝细胞癌细胞对阿霉素的重要耐药机制。然而，衣霉素和 Pae 联合预处理降低了 HCC 细胞中 COX-2 的表达和 Akt 的激活水平，并增加了 CHOP 的水平。我们的结果表明，Pae 通过靶向 COX-2 介导的 PI3K/AKT/CHOP 失活来逆转 ER 应激诱导的人肝细胞癌细胞对阿霉素的耐药性。
Endoplasmic reticulum stress (ER stress) is generally activated in solid tumors and results in tumor cell anti-apoptosis and drug resistance. Paeonol (Pae, 2-hydroxy-4-methoxyacetophenone), is a natural product extracted from the root of Paeonia Suffruticosa Andrew. Although Pae displays anti-neoplastic activity and increases the efficacy of chemotherapeutic drugs in various cell lines and in animal models, studies related to the effect of Pae on ER stress–induced resistance to chemotherapeutic agents in hepatocellular carcinoma (HCC) are poorly understood. In this study, we investigated the effect of the endoplasmic reticulum (ER) stress response during resistance of human hepatocellular carcinoma cells to doxorubicin. Treatment with the ER stress-inducer tunicamycin (TM) before the addition of doxorubicin reduced the rate of apoptosis induced by doxorubicin. Interestingly, co-pretreatment with tunicamycin and Pae significantly increased apoptosis induced by doxorubicin. Furthermore, induction of ER stress resulted in increasing expression of COX-2 concomitant with inactivation of Akt and up-regulation of the pro-apoptotic transcription factor CHOP (GADD153) in HepG2 cells. These cellular changes in gene expression and Akt activation may be an important resistance mechanism against doxorubicin in hepatocellular carcinoma cells undergoing ER stress. However, co-pretreatment with tunicamycin and Pae decreased the expression of COX-2 and levels of activation of Akt as well as increasing the levels of CHOP in HCC cells. Our results demonstrate that Pae reverses ER stress–induced resistance to doxorubicin in human hepatocellular carcinoma cells by targeting COX-2 mediated inactivation of PI3K/AKT/CHOP.
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影响因子：
5.1
作者：
Kapoor, Ashwani;Sanyal, Arun J.
通讯作者：
Sanyal, Arun J.
影响因子：
3.7
作者：
Lee HJ;Kim SA;Lee HJ;Jeong SJ;Han I;Jung JH;Lee EO;Zhu S;Chen CY;Kim SH
通讯作者：
Kim SH
影响因子：
29.4
作者：
Diehl JA;Fuchs SY;Koumenis C
通讯作者：
Koumenis C
DOI：
10.1083/jcb.201003138
发表时间：
2010-05-31
期刊：
The Journal of cell biology
影响因子：
--
作者：
Rutkowski DT;Hegde RS
通讯作者：
Hegde RS
影响因子：
3.7
作者：
Catalano, Rob D.;Wilson, Martin R.;Jabbour, Henry N.
通讯作者：
Jabbour, Henry N.