Restraint stress promotes lung cancer xenograft growth via the IL2-Ras-Erk pathway

Objectives: To assess the impact of restraint stress on lung cancer xenograft development, and explore the Molecular mechanism. Methods: We established a restraint stress model by placing nude mice in a ventilated 50 mL centrifuge tube and inoculating them with subcutaneous xenografts of the A549 lung cancer cell line on day 21. In order to verify the effects of IL2 on tumor growth, we treated A549 cells with IL2 (1 or 5 ng/mL) in vitro. Results: Compared with the non-stressed mice, the stressed mice exhibited lower body weight gain and larger tumors after 42 days of restraint stress treatment. The stressed mice also exhibited a higher level of proinflammatory cytokine IL2 in serum, tumor tissue, spleen and lymph nodes. The tumors from the stressed mice exhibited higher activity of the ras-extracellular signal-regulated kinase (Ras-Erk) signaling pathway. Compared with the control group (0 ng/mL), the cells treated with IL2 exhibited a higher rate of proliferation and migration, along with increased activity of the Ras-Erk pathway. Knockdown of the IL2 receptor by siRNA alleviated the increase of proliferation, migration and RAS-Erk pathway activity stimulated by IL2. Conclusion: Based on these findings, we conclude that restraint stress increased IL2 levels to promote tumor growth by activating the Ras-Erk pathway.