Esculentoside A Inhibits Lung Cancer Cell Migration and Invasion by Modulating Macrophage Polarization through IL-6/STAT3 Signaling Pathway

Abstract

Background: Tumor-associated macrophage (TAM) is pivotal in cancer progression. Esculentoside A (EsA) is a saponin extracted from plants, which has anti-cancer and anti-inflammatory effects. However, its anti-cancer effects through inhibiting TAM activation are still unclear and need further research. Methods: Human myeloid leukemia mononuclear cells (THP-1) differentiate into M2 macrophages under induction. The cultivation of A549 and H1299 cells was performed in a conditioned medium from M2 macrophages (M2-CM) to fathom the effects of EsA on viability of cancer cells and their abilities to migrate and invade. The macrophage markers were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and flow cytometry. Investigations on how EsA impacts interleukin (IL)-6/signal transducer and activator of transcription 3 (STAT3) signaling pathway were conducted by means of western blot and immunofluorescence. Results: Adherent and rounded THP-1 cells were observed through propidium monoazide (PMA) treatment. THP-1 cells expressed M1 macrophage markers with induction of lipopolysaccharide/interferon-γ and expressed M2 macrophage markers after induction of IL-13/IL-4 (p < 0.01). EsA may dampen IL-13/IL-4-induced M2 macrophage polarization as indicated by downregulation of the mRNA levels of CD206 (M2 macrophage marker) and peroxisome proliferator-activated receptor γ (PPARγ) (p < 0.001), and inhibit IL-6 expression in cells and STAT3 phosphorylation (p < 0.05). Moreover, EsA reversed M2-CM-induced promotion of lung cancer cell migration and invasion (p < 0.05). Conclusions: EsA inhibits lung cancer cell migration and invasion by mediating macrophage polarization through IL-6/STAT3 signaling pathway.