Wang Shaohui, Xu Xiaoling, Hu Yanlan, Lei Tao, Liu Tongxiang
Key Laboratory of Ethnomedicine (Minzu University of China), Minority of Education, Beijing, China.
Medical College, Qingdao Binhai University, Qingdao, China.
Front Pharmacol. 2019 Dec 5;10:1460. doi: 10.3389/fphar.2019.01460. eCollection 2019.
Non-small cell lung cancer (NSCLC) is a globally scaled disease with a high incidence and high associated mortality rate. Autophagy is one of the important physiological activities that helps to control cell survival, influences the dynamics of cell death, and which plays a crucial role in the pathophysiology of NSCLC. Sotetsuflavone is a naturally derived and occurring flavonoid, and previous studies have demonstrated that sotetsuflavone possesses potential anti-cancer activities. However, whether or not sotetsuflavone induces autophagy, as well as has effects and influences cell death in NSCLC cells remains unclear. Thus, in our study, we examined and elucidated the roles and underlying mechanisms of sotetsuflavone upon the dynamics of autophagy in NSCLC and . The results indicated that sotetsuflavone was able to inhibit proliferation, migration, and invasion of NSCLC cells. Mechanistically, sotetsuflavone was able to induce apoptosis by increasing the levels of expression of cytochrome C, cleaved-caspase 3, cleaved-caspase 9, and Bax, and contrastingly decreased levels of expression of Bcl-2. In addition, we also found that decreased levels of expression of cyclin D1 and CDK4 caused arrest of the G0/G1 phases of the cell cycle. Furthermore, we also found that sotetsuflavone could induce autophagy which in turn can play a cytoprotective effect on apoptosis in NSCLC. Sotetsuflavone-induced autophagy appeared related to the blocking of the PI3K/Akt/mTOR pathway. Our study demonstrated that sotetsuflavone significantly inhibited the growth of xenograft model inoculated A549 tumor with high a degree of safety. Taken together, these findings suggest that sotetsuflavone induces autophagy in NSCLC cells through its effects upon blocking of the PI3K/Akt/mTOR signaling pathways. Our study may provide a theoretical basis for future clinical applications of sotetsuflavone and its use as a chemotherapeutic agent for treatment of NSCLC.
非小细胞肺癌（NSCLC）是一种全球范围内发病率高且死亡率高的疾病。自噬是有助于控制细胞存活、影响细胞死亡动态并在NSCLC病理生理学中起关键作用的重要生理活动之一。大豆黄素是一种天然存在的类黄酮，先前的研究表明大豆黄素具有潜在的抗癌活性。然而，大豆黄素是否诱导自噬以及对NSCLC细胞的死亡是否有影响仍不清楚。因此，在我们的研究中，我们研究并阐明了大豆黄素在NSCLC自噬动态中的作用及潜在机制。结果表明，大豆黄素能够抑制NSCLC细胞的增殖、迁移和侵袭。机制上，大豆黄素能够通过增加细胞色素C、裂解的半胱天冬酶-3、裂解的半胱天冬酶-9和Bax的表达水平来诱导凋亡，相反降低Bcl-2的表达水平。此外，我们还发现细胞周期蛋白D1和细胞周期蛋白依赖性激酶4（CDK4）表达水平的降低导致细胞周期G0/G1期停滞。此外，我们还发现大豆黄素可诱导自噬，进而对NSCLC细胞凋亡发挥细胞保护作用。大豆黄素诱导的自噬似乎与PI3K/Akt/mTOR信号通路的阻断有关。我们的研究表明，大豆黄素能显著抑制接种A549肿瘤的异种移植模型的生长，且安全性高。综上所述，这些发现表明大豆黄素通过阻断PI3K/Akt/mTOR信号通路诱导NSCLC细胞自噬。我们的研究可能为大豆黄素未来的临床应用及其作为治疗NSCLC的化疗药物提供理论依据。
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