Curcumin Inhibits Prostate Cancer Metastasis in vivo by Targeting the Inflammatory Cytokines CXCL1 and -2

In America and Western Europe, prostate cancer is the second leading cause of death in men. Emerging evidence suggests that chronic inflammation is a major risk factor for the development and metastatic progression of prostate cancer. We previously reported that the chemopreventive polyphenol curcumin inhibits the expression of the proinflammatory cytokines CXCL1 and -2 leading to diminished formation of breast cancer metastases. In this study, we analyze the effects of curcumin on prostate carcinoma growth, apoptosis and metastasis. We show that curcumin inhibits translocation of NF κB to the nucleus through the inhibition of the IκB-kinase (IKK β, leading to stabilization of the inhibitor of NF κB, IκBα, in PC-3 prostate carcinoma cells. Inhibition of NF κB activity reduces expression of CXCL1 and -2 and abolishes the autocrine/paracrine loop that links the two chemokines to NF κB. The combination of curcumin with the synthetic IKK β inhibitor, SC-541, shows no additive or synergistic effects indicating that the two compounds share the target. Treatment of the cells with curcumin and siRNA-based knockdown of CXCL1 and -2 induce apoptosis, inhibit proliferation and downregulate several important metastasis-promoting factors like COX2, SPARC and EFEMP. In an orthotopic mouse model of hematogenous metastasis, treatment with curcumin inhibits statistically significantly formation of lung metastases. In conclusion, chronic inflammation can induce a metastasis prone phenotype in prostate cancer cells by maintaining a positive proinflammatory and prometastatic feedback loop between NF κB and CXCL1/-2. Curcumin disrupts this feedback loop by the inhibition of NF κB signaling leading to reduced metastasis formation in vivo.