Activating transcription factor 4 confers a multidrug resistance phenotype to gastric cancer cells through transactivation of SIRT1 expression.
Activating transcription factor 4 confers a multidrug resistance phenotype to gastric cancer cells through transactivation of SIRT1 expression.
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激活转录因子 4 通过反式激活 SIRT1 表达赋予胃癌细胞多药耐药表型。
DOI：
10.1371/journal.pone.0031431
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Wu K
中科院分区：
文献类型：
--
作者：
Zhu H;Xia L;Zhang Y;Wang H;Xu W;Hu H;Wang J;Xin J;Gang Y;Sha S;Xu B;Fan D;Nie Y;Wu K
胃癌的多药耐药（MDR）仍是临床治疗面临的主要挑战。转录激活因子4（Activating transcription factor 4，ATF 4）是一种应激反应基因，参与体内平衡和细胞保护。然而，ATF 4在胃癌MDR中的表达和功能尚不清楚。本研究旨在探讨ATF 4在胃癌多药耐药中的作用及其机制。我们证明，ATF 4过表达赋予胃癌细胞MDR表型，而在MDR变体中ATF 4的敲低诱导再致敏。在本研究中，我们还发现，NAD+依赖性组蛋白去乙酰化酶SIRT 1是需要ATF 4诱导胃癌细胞的MDR效应。我们证明ATF 4通过直接与SIRT 1启动子结合，导致SIRT 1上调，从而促进胃癌细胞的MDR。值得注意的是，通过小干扰RNA（siRNA）或特异性抑制剂（EX-527）抑制SIRT 1重新引入了治疗敏感性。同时，在ATF 4过表达的细胞中，Bcl-2/Bax比值和MDR 1表达水平增加。我们发现，ATF 4在调节胃癌细胞对化疗反应的MDR中具有关键作用，这些发现表明靶向ATF 4可以减轻胃癌的治疗耐药性。
Multidrug resistance (MDR) in gastric cancer remains a major challenge to clinical treatment. Activating transcription factor 4 (ATF4) is a stress response gene involved in homeostasis and cellular protection. However, the expression and function of ATF4 in gastric cancer MDR remains unknown. In this study, we investigate whether ATF4 play a role in gastric cancer MDR and its potential mechanisms. We demonstrated that ATF4 overexpression confered the MDR phenotype to gastric cancer cells, while knockdown of ATF4 in the MDR variants induced re-sensitization. In this study we also showed that the NAD+-dependent histone deacetylase SIRT1 was required for ATF4-induced MDR effect in gastric cancer cells. We demonstrated that ATF4 facilitated MDR in gastric cancer cells through direct binding to the SIRT1 promoter, resulting in SIRT1 up-regulation. Significantly, inhibition of SIRT1 by small interfering RNA (siRNA) or a specific inhibitor (EX-527) reintroduced therapeutic sensitivity. Also, an increased Bcl-2/Bax ratio and MDR1 expression level were found in ATF4-overexpressing cells. We showed that ATF4 had a key role in the regulation of MDR in gastric cancer cells in response to chemotherapy and these findings suggest that targeting ATF4 could relieve therapeutic resistance in gastric cancer.
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发表时间：
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