Abstract
BackgroundMorphine, 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.MethodsImmunofluorescence 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.ResultsMorphine 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/G2 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.ConclusionMorphine promotes the malignant biological behavior of H460 cells by activating the MOR and Src/mTOR signaling pathways.
Highlights
Lung cancer is the second most common cancer worldwide and the leading cause of cancer-related mortality
Migration and invasion of H460 cells We investigated whether MOR is expressed in nonsmall cell lung cancer (NSCLC) by performing immunofluorescence staining to determine the widespread distribution of MOR in BEAS-2B and H460 cells (Fig. 1a)
We found that morphine can increase the number of cells in S phase and decrease the population of cells in G2 phase, which proves that morphine can block the transition of cells from S to G2 phase, but there is no significant difference in propidium iodide (PI), indicating that morphine does not promote cell proliferation through affecting the cell cycle in H460 cells
Summary
Lung cancer is the second most common cancer worldwide and the leading cause of cancer-related mortality. Non-small cell lung cancer (NSCLC) accounts for 85–90% of all cases, Liu et al Cancer Cell International (2021) 21:622 and the main treatment methods include surgery, radiation therapy, chemotherapy, and immunotherapy [3]. Morphine is a commonly used clinical drug for both surgical resection and pain treatment in patients with advanced lung cancer [4]. It exerts direct effects on the viability and migration of breast cancer cells. The mechanism underlying the effects of morphine on cancer cells remains unclear. 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
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