Resveratrol suppresses breast cancer proliferation through inhibition of stat3 activation and m2-macrophage polarization

Abstract

Background: Tumor-associated macrophages (TAM), M1 and M2 macrophages, are the most abundant leukocyte population that play critical role in breast cancer progression. M1 macrophages inhibit tumor growth while M2 macrophages enhance tumor progression. Resveratrol, a naturally occurring polyphenolic compound, is well known for its antitumor effect by targeting several cancer-related inflammatory pathways. This study aimed to investigate the effect of resveratrol on TAM polarization in breast cancer progression. Methods: The antitumor effect of resveratrol was examined in MDA-MB-231(MB231) and cisplatin resistance MDA-MB-231 (cisR) cells by cell proliferation assay using MTT. Gene expressions of M1 and M2 markers in macrophages derived from THP-1 cells, treated with tumor-conditioned medium (TCM) with or without resveratrol, were examined by qPCR and immunofluorescence (IF) staining. Cytokine profile of TCM was examined by Qiagen Multi-Analyte ELISArray and expression of cytokines in TCM was validated by qPCR. Expression of potential downstream targets of resveratrol were examined by western blot analysis. Result: Resveratrol significantly reduced cell proliferation and enhanced chemosensitivity in MB231 and cisR cells. Resveratrol inhibited CD163 (M2 marker) and increased CXCL10 and iNOS (M1 marker) expression. Downregulation of ARG1 (M2 marker) was also observed by IF staining. In addition, resveratrol decreased exogenous IL-1A and IL-6 levels in TCM. Moreover, resveratrol significantly decreased phosphorylation of STAT3 in cells. Conclusions: Our data demonstrated that resveratrol suppressed breast cancer cell proliferation by inhibiting M2-macrophage polarization and STAT3 activation through reducing the secretion of IL-1A and IL-6. This study revealed a novel mechanism on resveratrol-mediated macrophage polarization on breast cancer progression.