Adipocyte-Derived Monocyte Chemotactic Protein-1 (MCP-1) Promotes Prostate Cancer Progression Through the Induction of MMP-2 Activity

作者：Ito Yusuke; Ishiguro Hitoshi; Kobayashi Naohito; Hasumi Hisashi; Watanabe Masatoshi; Yao Masahiro; Uemura Hiroji^*

来源：Prostate, 2015, 75(10): 1009-1019.

DOI：10.1002/pros.22972

• prostate cancer
• adipocyte
• MCP-1
• invasion
• MMP-2

BACKGROUND. Obesity is known to be associated with prostate cancer development and progression, but the detailed mechanism is not clear. Monocyte chemotactic protein-1 (MCP-1) is secreted from cancer cells, stromal cells, and adipocytes, and it is involved in prostate cancer progression. Here we investigated the biological role of MCP-1 secreted from adipocytes for prostate cancer cells.
METHODS. Human pre-adipocytes (HPAds) were cultured and differentiated to mature adipocytes. Conditioned medium (CM) from HPAd cells was obtained using phenol red-free RPMI1640 medium. We performed a cytokine membrane array analysis to detect cytokines in the CM. To characterize the physiological function of MCP-1 in the CM, we performed an MTT-assay, a wound-healing and invasion assay with anti-MCP-1 antibody using three prostate cancer cell lines: DU145, LNCaP, and PC-3. Matrix metalloproteinase (MMP)-2 and MMP-9 activities were evaluated by gelatin zymography. A qPCR and Western blotting were used to examine the mRNA and protein expression levels of MMP-2.
RESULTS. The cytokine membrane array of the CM showed a strong signal of MCP-1compared to the control medium, and we thus focused our attention on MCP-1 in the CM. The CM up-regulated the cancer cell proliferation, and the neutralization by anti-MCP-1 antibody inhibited the proliferative effect of the prostate cancer cell lines. The CM greatly increased the invasive activity in the prostate cancer cell lines, and anti-MCP-1 antibody decreased the invasiveness. Gelatin zymography revealed that the CM markedly enhanced the enzymatic activity of MMP-2, and anti-MCP-1 antibody down-regulated its effect. MMP-2 mRNA expression was undetected and the MMP-2 protein level was unchanged between the control medium and CM in DU145 cells.
CONCLUSIONS. MCP-1 from adipocytes enhances the growth and invasion activity of prostate cancer cells. The inhibition of MCP-1 derived from adipocytes might be an effective treatment for prostate cancer.

• 出版日期2015-7-1