β-elemene regulates endoplasmic reticulum stress to induce the apoptosis of NSCLC cells through PERK/IRE1α/ATF6 pathway
β-elemene regulates endoplasmic reticulum stress to induce the apoptosis of NSCLC cells through PERK/IRE1α/ATF6 pathway
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β-榄香烯通过PERK/IRE1 α/ATF6通路调节内质网应激诱导NSCLC细胞凋亡
DOI：
10.1016/j.biopha.2017.06.073
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发表时间：
2017-09-01
影响因子：
7.5
通讯作者：
Feng, Liang
中科院分区：
文献类型：
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作者：
Liu, Ying;Jiang, Zi-yu;Feng, Liang
内质网应激（ERs）被认为是非小细胞肺癌（NSCLC）发病的重要原因。 β-榄香烯是从温郁金草药中提取的精油中的活性成分，据报道可有效对抗非小细胞肺癌 (NSCLC)。然而，β-榄香烯通过调节 ER 抑制 NSCLC 的潜在作用和潜在机制仍不清楚。在本研究中，建立了A549细胞和Lewis荷瘤C57BL/6J小鼠来评估这种效果。采用Visualsonics Vevo 2100小动物专用高频彩色超声观察体内肿瘤体积。使用3-(4,5-二甲基噻唑-2-基)-2,5-二苯基溴化四唑(MTT)评估A549细胞的细胞活力。此外，应用蛋白质印迹（WB）、免疫组织化学（IHC）和定量逆转录聚合酶链反应（q-PCR）来检测ER相关蛋白。流式细胞术还用于检测细胞凋亡和活性氧（ROS）产生的检测试剂盒。我们的结果表明，β-榄香烯以剂量和时间依赖性方式抑制肺癌肿瘤生长和细胞活力。不仅如此，β-榄香烯还可以上调 ER 相关蛋白，如 PERK、IRE1 α、ATF6、ATF4、CHOP 并下调 Bcl-2 表达。更重要的是，ERs抑制剂4-PBA、IRE1α抑制剂STF-083010、ATF6抑制剂Anti-ATF6和PERK抑制剂GSK2656157均可降低蛋白表达变化幅度和细胞凋亡率，从而减弱β-榄香烯的抗肿瘤作用。因此，目前的体内和体外研究表明，β-榄香烯的抗NSCLC作用与通过PERK/IRE1α/ATF6通路激活ER密切相关，这可能有益于NSCLC的临床治疗。 (C) 2017 Elsevier Masson SAS。版权所有。
Endoplasmic reticulum stress (ERs) has been regarded as an important cause for the pathogenesis of non-small-cell lung cancer (NSCLC). beta-elemene is an active component in the essential oil extracted from a medicinal herb, Curcuma wenyujin, and has been reported to be effective against non-small-cell lung cancer (NSCLC). However, the potential effect and underlying mechanisms of beta-elemene on regulating ERs to inhibit NSCLC are still unclear. In the present study, A549 cells and Lewis tumor-bearing C57BL/6J mice were established to evaluate this effect. Visualsonics Vevo 2100 Small Animal Dedicated High-frequency Color Ultrasound was performed to observe tumor volume in vivo. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) was used to evaluate cell vitality of A549 cells. Furthermore, western blotting (WB), immunohistochemistry (IHC) and quantitative reverse transcription polymerase chain reaction (q-PCR) were applied to detect the ERs-related proteins. Flow cytometry was also applied to detect cell apoptosis and assay kit for reactive oxygen species (ROS) generation. Our results showed that beta-elemene inhibited lung cancer tumor growth and cell vitality in a dose-and time-dependent manner. Not only that, beta-elemene could up-regulate ERs-related proteins like PERK, IRE1 alpha, ATF6, ATF4, CHOP and down-regulate the Bcl-2 expression. More importantly, ERs inhibitor 4-PBA, IRE1 alpha inhibitor STF-083010, ATF6 inhibitor Anti-ATF6 and PERK inhibitor GSK2656157 can all reduce the amplitude of protein expression changes and apoptosis rates, then weaken the anti-tumor effect of beta-elemene. Therefore, the present in vivo and in vitro study revealed that the anti-NSCLC effect of beta-elemene is closely related to the activation of ERs through PERK/IRE1 alpha/ATF6 pathway, and this might be beneficial for clinical therapy of NSCLC. (C) 2017 Elsevier Masson SAS. All rights reserved.