Resveratrol Exerts Inhibitory Effects on the Growth and Metastasis of Lung Cancer and Modulates the Polarization of Tumor-Associated Neutrophils

Abstract

Background: The resveratrol (RES) exhibits inhibitory effects against lung cancer through various targets. However, the exact underlying mechanism remains unclear. This study aims to investigate the effect of RES on the growth and metastasis of lung cancer and its impact on polarization of tumor-associated neutrophils (TANs) and epithelial-mesenchymal transition (EMT). Method: The A549 lung cancer cell line was treated with varying concentrations (0, 5, 10, 20, 40, and 60 μM) of RES. The impact of RES on cellular proliferation was assessed using Cell Counting Kit-8 (CCK-8) assay, and the optimal dosage was selected for subsequent analysis. Furthermore, the effects of RES treatment on the apoptosis, invasion, and migration of the cells, along with its impact on the EMT process, were examined. Neutrophils were isolated from the blood of the health individuals and were co-cultured with A549 cells to investigate the TANs polarization. Additionally, we established a nude mouse model of the subcutaneous tumor. The lung cancer growth, tumor tissue pathology, and tumor cell metastasis were evaluated. Results: We observed that RES effectively suppressed A549 cell growth in a concentration-dependent manner within the dosage range of 10–40 μM (p < 0.001). Furthermore, RES promoted A549 cell apoptosis while limiting invasion and migration (p < 0.001). Moreover, RES was observed to regulate the EMT pathway in A549 cells, thereby limiting its progression (p < 0.01). Notably, RES restricted lung cancer by inducing TANs to polarize toward type N1 while impeding type N2 polarization (p < 0.001). In the nude mouse model, RES demonstrated the above-mentioned effects and considerably reduced lung cancer growth, improved tumor tissue pathology, and limited tumor growth (p < 0.01), as well as reduced the expression of Matrix Metalloproteinase-2 (MMP2) and MMP9 (p < 0.05). Conclusion: Overall, RES effectively reduces lung cancer growth and tumor cell metastasis by boosting N1 polarization of TAN, suppressing N2 polarization, and reducing EMT.