Department of Gastroenterology and State Key Laboratory of Cancer Biology, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
PLoS One. 2012;7(2):e31431. doi: 10.1371/journal.pone.0031431. Epub 2012 Feb 17.
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.
METHODOLOGY/PRINCIPAL FINDINGS: 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.
CONCLUSIONS/SIGNIFICANCE: 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.
胃癌的多药耐药（MDR）仍然是临床治疗的主要挑战。激活转录因子 4（ATF4）是一种参与体内平衡和细胞保护的应激反应基因。然而，ATF4 在胃癌 MDR 中的表达和功能尚不清楚。在本研究中，我们研究了 ATF4 是否在胃癌 MDR 中发挥作用及其潜在机制。
方法/主要发现：我们证明 ATF4 的过表达赋予了胃癌细胞 MDR 表型，而在 MDR 变体中敲低 ATF4 则诱导重新敏感化。在这项研究中，我们还表明，NAD（+）依赖性组蛋白去乙酰化酶 SIRT1 是 ATF4 在胃癌细胞中诱导 MDR 效应所必需的。我们证明，ATF4 通过直接结合 SIRT1 启动子促进胃癌细胞中的 MDR，导致 SIRT1 上调。值得注意的是，通过小干扰 RNA（siRNA）或特异性抑制剂（EX-527）抑制 SIRT1 可重新引入治疗敏感性。此外，在 ATF4 过表达的细胞中发现 Bcl-2/Bax 比值和 MDR1 表达水平增加。
结论/意义：我们表明，ATF4 在化疗诱导的胃癌细胞 MDR 调节中起关键作用，这些发现表明靶向 ATF4 可能缓解胃癌的治疗耐药性。
