KiSS1 Suppresses TNFα-Induced Breast Cancer Cell Invasion Via an Inhibition of RhoA-Mediated NF-κB Activation

Tumor necrosis factor-alpha (TNF alpha) induces cancer development and metastasis, which is prominently achieved by nuclear factor-kappa B (NF-kappa B) activation. TNF alpha-induced NF-kappa B activation enhances cellular mechanisms including proliferation, migration, and invasion. KiSS1, a key regulator of puberty, was initially discovered as a tumor metastasis suppressor. The expression of KiSS1 was lost or down-regulated in different metastatic tumors. However, it is unclear whether KiSS1 regulates TNF alpha-induced NF-kappa B activation and further tumor cell migration. In this study, we demonstrate that KiSS1 suppresses the migration or breast cancer cells by inhibiting TNF alpha-induced NF-kappa B pathway and RhoA activation. Both KiSS1 overexpression and KP10 (kisspeptin-10) stimulation inhibited TNF alpha-induced NF-kappa B activity, suppressed TNF alpha-induced cell migration and cell attachment to fibronectin in breast cancer cells while KP10 has little effect on cancer cell proliferation. Furthermore, KP10 inhibited TNF alpha-induced cell migration and RhoA GTPase activation. Therefore, our data demonstrate that KiSS1 inhibits TNF alpha-induced NF-kappa B activation via downregulation of RhoA activation and suppression of breast cancer cell migration and invasion. J. Cell. Biochem. 107: 1139-1149, 2009. (C) 2009 Wiley-Liss, Inc.