Propofol Attenuates Lung but not Brain Cancer Cell Malignancy through Metabolism and Cell Signaling Modulation In Vitro

Abstract Background: Intravenous anesthesia with propofol was reported to improve cancer surgical outcomes when compared with inhalational anesthesia. However, the underlying molecular mechanisms largely remain unknown. The current study aims to investigate whether propofol affects cancer cell biology including tumor metastasis-related gene expression, cellular signaling and metabolic changes in lung and brain cancer cells.Methods: Lung cancer (A549) or neuroglioma (H4) cells were treated with propofol at a clinically relevant concentration (4 μg/mL) for 2 hours, followed by 24 hours recovery. Tumor metastasis-related gene expressions were assessed using a PCR array and validated with qRT-PCR. Glucose transporter 1 (GLUT1), brain protein 44-like (BRP44L), pigment epithelium-derived factor (PEDF), Akt, phospho-Akt (p-Akt), extracellular-signal-regulated kinase 1/2 (Erk1/2), phospho-Erk1/2 (p-Erk1/2), and hypoxia-inducible factor 1 alpha (HIF-1α) expressions were determined using immunofluorescent staining and/or western blotting. The metabolites in cell extract and media following propofol treatment were characterized using proton nuclear magnetic resonance ( 1 H NMR) spectroscopy. The malignant hallmarks including cell viability, proliferation, migration, and invasion were evaluated using cell counting kit-8 (CCK-8) assay, Ki-67 staining, wound healing and transwell assay, respectively.Results: Propofol reduced cell viability and inhibited cell proliferation, migration and invasion of lung cancer cells, but not neuroglioma cells. In lung cancer cells, gene expressions of VEGFA, CTBP1, CST7, CTSK, CXCL12, and CXCR4 were downregulated, while NR4A3, RB1, NME1, MTSS1, NME4, SYK, APC, and FAT1 were upregulated following the propofol treatment. Furthermore, propofol downregulated GLUT1, BRP44L, p-Akt, p-Erk, and HIF-1α expressions in lung cancer cells and upregulated PEDF expression. Propofol increased glutamate and glycine but decreased acetate and formate in lung cancer cells whilst increased lactate, valine, isoleucine, and leucine and glycerol, and decreased pyruvate and isopropanol in the culture media. Consistent with the phenotypical changes, these molecular and metabolic changes were not observed in the neuroglioma cells.Conclusions: Our findings indicated “anti-tumor” effects of propofol on the lung cancer but not neuroglioma, through the regulation of tumor metastasis-related genes, multi-cellular signaling and cellular metabolism.