Liu Xingyun, Yang Jia, Yang Chengwei, Huang Xiang, Han Mingming, Kang Fang, Li Juan
Department of Anesthesiology, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei, 230036, China.
Department of Anesthesiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230036, China.
Cancer Cell Int. 2021 Nov 25;21(1):622. doi: 10.1186/s12935-021-02334-8.
Morphine, a µ-opioid receptor (MOR) agonist, has been shown to be related to the activity of cancer cells, and a higher morphine dosage reduces the survival time of patients with lung cancer. However, the effect of morphine on the malignant behavior of lung cancer cells remains unclear. The aim of this study was to investigate the specific molecular mechanism by which morphine regulates the malignant biological behavior of non-small cell lung cancer.
Immunofluorescence staining and Western blot analyses were performed to detect MOR expression. H460 non-small cell lung cancer cells were used in this study, and cell proliferation, the cell cycle and apoptosis were evaluated using Cell Counting Kit-8 (CCK-8) and flow cytometry assays, respectively. Cell migration and invasion were detected using wound healing and Transwell assays. The effect of morphine on lung cancer development in vivo was examined by performing a xenograft tumor assay following morphine treatment.
Morphine promoted the growth of H460 cells both in vivo and in vitro. Morphine enhanced cell migration and invasion, modified cell cycle progression through the S/G transition and exerted an antiapoptotic effect on H460 cells. Additionally, morphine increased Rous sarcoma oncogene cellular homolog (Src) phosphorylation and activated the phosphoinositide 3 kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway. Treatment with the MOR antagonist methylnaltrexone (MNTX) and the Src inhibitor protein phosphatase 1 (PP1) reduced the phosphorylation induced by morphine. Furthermore, MNTX, PP1, and the PI3K/AKT inhibitor deguelin reversed the antiapoptotic effect of morphine on lung cancer cells.
Morphine promotes the malignant biological behavior of H460 cells by activating the MOR and Src/mTOR signaling pathways.
吗啡作为一种μ-阿片受体（MOR）激动剂，已被证明与癌细胞活性有关，较高剂量的吗啡会缩短肺癌患者的生存时间。然而，吗啡对肺癌细胞恶性行为的影响仍不清楚。本研究旨在探讨吗啡调节非小细胞肺癌恶性生物学行为的具体分子机制。
采用免疫荧光染色和蛋白质免疫印迹分析检测MOR表达。本研究使用H460非小细胞肺癌细胞，分别采用细胞计数试剂盒-8（CCK-8）和流式细胞术检测细胞增殖、细胞周期和凋亡情况。采用伤口愈合试验和Transwell试验检测细胞迁移和侵袭能力。通过对吗啡处理后的异种移植瘤试验，研究吗啡对体内肺癌发展的影响。
吗啡在体内和体外均促进H460细胞生长。吗啡增强细胞迁移和侵袭能力，通过S/G期转换改变细胞周期进程，并对H460细胞发挥抗凋亡作用。此外，吗啡增加罗氏肉瘤癌基因细胞同源物（Src）磷酸化，并激活磷脂酰肌醇3激酶（PI3K）/蛋白激酶B（AKT）/雷帕霉素哺乳动物靶蛋白（mTOR）信号通路。用MOR拮抗剂甲基纳曲酮（MNTX）和Src抑制剂蛋白磷酸酶1（PP1）处理可降低吗啡诱导的磷酸化水平。此外，MNTX、PP1和PI_3K/AKT抑制剂地谷新可逆转吗啡对肺癌细胞的抗凋亡作用。
吗啡通过激活MOR和Src/mTOR信号通路促进H460细胞的恶性生物学行为。
