(-)-Guaiol regulates autophagic cell death depending on mTOR signaling in NSCLC
(-)-Guaiol regulates autophagic cell death depending on mTOR signaling in NSCLC
复制标题
(-)-愈创木酚通过 NSCLC 中的 mTOR 信号传导调节自噬细胞死亡
DOI：
10.1080/15384047.2018.1451277
复制
发表时间：
2018
影响因子：
3.6
通讯作者：
Yang Qingyuan
中科院分区：
文献类型：
--
作者：
Yang Xiaohui;Zhu Jiabei;Wu Jianchun;Huang Nan;Cui Zhongqi;Luo Yingbin;Sun Fenyong;Pan Qiuhui;Li Yan;Yang Qingyuan
（-）-愈创木酚是一种具有愈创木烷骨架的倍半萜醇，已在许多中国药用植物中发现，并据报道包含各种愈创木烷天然产物，这些天然产物因其抗菌活性而众所周知。以前，我们已经通过诱导NSCLC细胞中的自噬显示了其抗肿瘤活性。然而，其诱导自噬的潜在机制仍在我们的研究中。在这里，我们的蛋白质印迹分析的数据显示，在NSCLC细胞中，（-）-愈创木酚通过抑制mTOR在丝氨酸2481（S2481）处的磷酸化来诱导自噬，从而显著阻断mTORC 2-AKT信号传导，这通过LC 3 II/I的比率增加来说明。此外，它还通过抑制mTORC 1的下游因子4 E-BP 1和p70 S6 K的活性而使mTORC 1信号通路受损，mTOR激活剂MHY 1485可明显挽救mTORC 1信号通路。之后，生物功能测定的结果，包括细胞存活分析、集落形成测定和流式细胞术测定，表明（−）-愈创木酚通过靶向mTORC 1和mTORC 2信号通路触发自噬细胞死亡。总之，我们的研究表明，（−）-愈创木酚通过特异性靶向mTOR信号通路（包括mTORC 1和mTORC 2信号通路）抑制NSCLC细胞增殖，为替代雷帕霉素治疗NSCLC患者提供了更好的治疗选择。
(−)-Guaiol, a sesquiterpene alcohol with the guaiane skeleton, has been found in many Chinese medicinal plants and been reported to comprise various guaiane natural products that are well known for their antibacterial activities. Previously, we have shown its antitumor activity by inducing autophagy in NSCLC cells. However, its potential mechanism in inducing autophagy is still under our investigation. Here, data from our western blotting assays showed that, in NSCLC cells, (−)-Guaiol significantly blocked the mTORC2-AKT signaling by suppressing mTOR phosphorylation at serine 2481 (S2481) to induce autophagy, illustrated by the increasing ratio of LC3II/I. Besides, it impaired the mTORC1 signaling by inhibiting the activity of its downstream factors, such as 4E-BP1 and p70 S6K, all of which could obviously rescued by the mTOR activator MHY1485. Afterwards, results from biofunctional assays, including cell survival analysis, colony formation assays and flow cytometry assays, suggested that (−)-Guaiol triggered autophagic cell death by targeting both mTORC1 and mTORC2 signaling pathways. In summary, our studies showed that (−)-Guaiol inhibited the proliferation of NSCLC cells by specifically targeting mTOR signaling pathways, including both mTORC1 and mTORC2 signaling, providing a better therapeutic option for substituting rapamycin in treating NSCLC patients.