Inflammatory suppressive effect of prostate cancer cells with prolonged exposure to transforming growth factor β on macrophage-differentiated cells via downregulation of prostaglandin E(2)

Transforming growth factor β1 (TGFβ1) regulates a variety of cellular functions, including cell growth, apoptosis and differentiation. The aim of the current study was to investigate the alterations of phenotypic events in the long-term exposure of prostate cancer (PCa) cells to TGFβ1 and its effect on macrophage-differentiated cells. The PCa cell line, PC-3, and the subclone, M1, were exposed to TGFβ1 for short- or long-term periods. TGFβ1 signaling was assessed by Smad3 phosphorylation, and non-canonical signaling was analyzed by quantitative polymerase chain reaction-based regulatory gene expression profiles. TGFβ1-exposed PCa cells were also co-cultured with phorbol 12-myristate 13-acetate (PMA)-treated THP-1 macrophages as a model of the tumor microenvironment. The phosphorylation of Smad3 in the PCa cells with long-term exposure was lower than that in the PCa cells with short-term exposure. Interleukin-6 mRNA expression in the PMA-treated THP-1 macrophages was significantly downregulated by co-culture with the PCa cells with long-term exposure. Cyclooxygenase-2 expression in the long-term TGFβ1-exposed PCa cells was lower than that in the control PCa cells, and the production of prostaglandin E(2) (PGE(2)) in the long-term TGFβ1-exposed PCa cells was also significantly lower. The results of the current study demonstrated that the long-term TGFβ1 exposure of PCa cells induces phenotypic changes, including the downregulation of PGE(2) production. This indicates that prolonged TGFβ-exposed PCa cells may change the cytokine production of macrophages in the tumor microenvironment.