Scutebarbatine A inhibits M2 macrophage polarization via blocking PI3K/AKT signaling to impair cell stemness, metastasis, and angiogenesis in non-small cell lung cancer.

[BACKGROUND] Tumor-associated macrophages are an important component of tumor microenvironment, and M2-like macrophages have been affirmed to promote tumor growth and development. Scutebarbatine A exhibits anti-tumor activity in non-small cell lung cancer (NSCLC). This study focused on the effect and mechanism of Scutebarbatine A on M2 macrophage polarization in NSCLC.

[METHODS] Flow cytometry was used to detect M1/M2-related marker expression. Real-time quantitative polymerase chain reaction and Western blot were utilized for detection of mRNA and protein, respectively. The potential targets of Scutebarbatine A in M2 macrophage polarization in NSCLC were predicted by online databases and Venny analysis. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to screen the significant pathway. After NSCLC cells were co-cultured with conditioned medium from macrophages, cell function was examined by Cell Counting Kit-8 (CCK-8), colony formation assay, sphere formation assay, transwell assay, and tube formation assay. Xenograft tumor models were established to explore the effect of Scutebarbatine A on M2 macrophage polarization in vivo.

[RESULTS] Scutebarbatine A intervened the polarization of M2 macrophages. Mechanistically, Scutebarbatine A suppressed M2 macrophage polarization via association with phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway. Additionally, Scutebarbatine A alleviated the promoting effects of M2 macrophages on stemness, migration, invasion, and angiogenesis of NSCLC cells by affecting PI3K/AKT pathway. Scutebarbatine A also reduced tumor growth caused by M2 macrophages in vivo.

[CONCLUSION] Altogether, this study suggested that anti-tumor activity of Scutebarbatine A in NSCLC progression was associated with regulation of PI3K/AKT pathway and M2 macrophage polarization, uncovering previously undiscovered role and mechanism of Scutebarbatine A.