Curcumin Inhibits Prostate Cancer Metastasis in vivo by Targeting the Inflammatory Cytokines CXCL1 and -2
Menée sur une lignée cellulaire humaine de carcinome de la prostate et à l'aide d'un modèle murin orthotopique de métastases hématogènes, cette étude montre que la curcumine, un pigment polyphénolique provenant du Curcuma longa, peut bloquer le processus métastatique en agissant sur la boucle de régulation des cytokines de l'inflammation CXCL1 et CXCL2
Résumé en anglais
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 pro-inflammatory cytokines CXCL1 and -2 leading to diminished formation of breast cancer metastases. Here we analyse the effects of Curcumin on prostate carcinoma growth, apoptosis and metastasis. We show that Curcumin inhibits translocation of NFκB to the nucleus through the inhibition of the IκB-kinase, IKKβ, leading to stabilization of the inhibitor of NFκB, IκBα, in PC3 prostate carcinoma cells. Inhibition of NFκB activity reduces expression of CXCL1 and -2 and abolishes the autocrine/paracrine loop that links the two chemokines to NFκB. The combination of Curcumin with the synthetic IKKβ inhibitor, SC-541, shows no additive or synergistic effects indicating that the two compounds share the target. Treatment of the cells with Curcumin as wells as siRNA based knock-down of CXCL1 and -2 induce apoptosis, inhibit proliferation, and down-regulate several important metastasis-promoting factors like COX2, SPARC, and EFEMP. In an orthotopic mouse model of haematogenous 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 pro-inflammatory and pro-metastatic feed-back loop between NFκB and CXCL1/-2. Curcumin disrupts this feed-back loop by the inhibition of NFκB signalling leading to reduced metastasis formation in vivo.
