School of Preclinical and Forensic Medicine, Sichuan University, Chengdu 610041, PR China; Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, PR China.
Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, PR China.
Toxicol Appl Pharmacol. 2022 Jun 1;444:116037. doi: 10.1016/j.taap.2022.116037. Epub 2022 Apr 27.
Lung carcinoma is the leading cause of cancer-related death worldwide. Chemotherapy remains the cornerstone of lung cancer treatment. Unfortunately, most types of cancer will develop resistance to chemotherapies over the time. One of the efforts to prevent the chemotherapy resistance is to find alternative chemotherapy drugs. Mogrol has been found to have antitumor activity. However, little is known about the pharmacological mechanisms underlying the suppression of mogrol on lung cancers. In this study, we observed that mogrol exposure significantly reduced the tumor volume and weight in tumor-bearing nude mice without obvious effect on body weight and cardiac function. Mogrol also significantly inhibited the proliferation and migration of lung cancer cells, including non-small-cell lung carcinoma cells, A549, H1299, H1975 and SK-MES-1 cells, with no obvious effect on control human bronchial epithelial cells (HBE). Further studies revealed that mogrol stirred excessive autophagy and autophagic flux, and finally, autophagic cell death, in lung cancer cells, which could be attenuated by autophagy inhibitors, 3-MA and chloroquine. Furthermore, mogrol significantly activated AMPK to induce autophagy and autophagic cell death, which could be abrogated by Compound C, an AMPK inhibitor. In addition, mogrol induced a significant increase in p53 activity in lung cancer cells, accompanied with cell cycle arrest and apoptosis, which could be weakened by p53 silence. Our results indicated that mogrol effectively suppressed lung cancer cells in vivo and in vitro by inducing the excessive autophagy and autophagic cell death via activating AMPK signaling pathway, as well as cell cycle arrest and apoptosis via activating p53 pathway.
肺癌是全球癌症相关死亡的主要原因。化疗仍然是肺癌治疗的基石。不幸的是，随着时间的推移，大多数类型的癌症都会对化疗产生耐药性。预防化疗耐药性的努力之一是寻找替代化疗药物。已经发现莫咯醇具有抗肿瘤活性。然而，关于莫咯醇抑制肺癌的药理学机制知之甚少。在这项研究中，我们观察到莫咯醇暴露显著减少了荷瘤裸鼠的肿瘤体积和重量，而对体重和心脏功能没有明显影响。莫咯醇还显著抑制了肺癌细胞的增殖和迁移，包括非小细胞肺癌细胞 A549、H1299、H1975 和 SK-MES-1 细胞，对对照人支气管上皮细胞（HBE）没有明显影响。进一步的研究表明，莫咯醇在肺癌细胞中引发了过度的自噬和自噬流，并最终导致自噬细胞死亡，自噬抑制剂 3-MA 和氯喹可以减弱这种作用。此外，莫咯醇显著激活 AMPK 诱导自噬和自噬细胞死亡，AMPK 抑制剂 Compound C 可以阻断这种作用。此外，莫咯醇诱导肺癌细胞中 p53 活性显著增加，伴随细胞周期停滞和凋亡，p53 沉默可以减弱这种作用。我们的研究结果表明，莫咯醇通过激活 AMPK 信号通路诱导过度自噬和自噬细胞死亡，以及通过激活 p53 通路诱导细胞周期停滞和凋亡，有效抑制了体内和体外的肺癌细胞。
