The inflammatory macrophages repress the growth of bone metastatic human prostate cancer cells via TNF-α and IL-6 signaling: Involvement of cell signaling regulator regucalcin.

Macrophages in the cancer microenvironments may play a regulatory role in the progression and metastasis of prostate cancer cells. However, the crosstalk between macrophages and prostate cancer cells is poorly understood. This study elucidates whether inflammatory macrophages regulate the proliferation and death of human prostate cancer cells in vitro. The RAW264.7 mouse macrophages were cocultured with PC-3 or DU-145 wild-type cells by using a Transwell chamber in vitro. RAW264.7 cells were cocultured with PC-3 or DU-145 cells in the presence of lipopolysaccharide (LPS). This coculturing blocked the proliferation and accelerated the death of cancer cells. Interestingly, cancer cell proliferation was repressed and death was promoted by the addition of the conditioned medium obtained from RAW264.7 cells treated with LPS. Culturing with LPS mostly augmented the production of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the culture medium of RAW264.7 cells. The effects of the conditioned medium on the proliferation and death of PC-3 or DU-145 cells were blocked by NF-κB or STAT3 signaling inhibitors. Moreover, the effects of the conditioned medium on the proliferation and death of prostate cancer cells were not expressed in regucalcin-overexpressing cancer cells that diminish the levels of NF-κB p65 and STAT3. Culturing with extracellular TNF-α, IL-6, or regucalcin triggered inhibition of the proliferation of PC-3 wild-type cells. The levels of regucalcin in PC-3 cells were elevated by TNF-α or IL-6 stimulation. This study demonstrates that inflammatory macrophages triggered the loss of prostate cancer cells via the signaling process of NF-κB, STAT3, or regucalcin.