Sevoflurane activates the IL-6/HO-1 pathway to promote macrophage M2 polarization and prostate cancer lung metastasis

Sevoflurane (Sev) is commonly used for cancer surgeries, but its effect on cancer cell biology remains unclear. This study aims to delineate the mechanistic actions underlying the oncogenic and metastatic potential of Sev on macrophage M2 polarization and lung metastasis in prostate cancer (PCa). We performed bioinformatics analysis to predict Sev- and PCa-related targets HO-1 and IL-6, and validated their expression in response to Sev exposure. The culture supernatant of macrophages differentiated from mouse bone marrow was co-cultured with mouse PCa cell line RM-1. HO-1 and IL-6 was found to be upregulated in macrophages exposed to Sev. Ectopic expression or knockdown of HO-1 and IL-6 was introduced to macrophages to probe their effect on macrophage polarization, migratory and invasive capacities of PCa cells and lung metastasis in tumor-bearing mice. It was demonstrated that Sev augmented macrophage M2 polarization and migratory and invasive potential of PCa cells as well as lung metastasis, which was associated with HO-1 upregulation. Mechanistic investigation indicated that Sev elevated IL-6 expression to enhance HO-1 expression. In vivo experiments verified that Sev facilitated macrophage M2 polarization and lung metastasis of RM-1 cells via IL-6/HO-1 in mice. Taken together, our work reveals a novel IL-6/HO-1-mediated regulatory network underlying Sev function that may be a viable target for preventing lung metastasis of PCa.