KiSS1 suppresses TNFalpha-induced breast cancer cell invasion via an inhibition of RhoA-mediated NF-kappaB activation.

Tumor necrosis factor-alpha (TNFalpha) induces cancer development and metastasis, which is prominently achieved by nuclear factor-kappa B (NF-kappaB) activation. TNFalpha-induced NF-kappaB 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 TNFalpha-induced NF-kappaB activation and further tumor cell migration. In this study, we demonstrate that KiSS1 suppresses the migration of breast cancer cells by inhibiting TNFalpha-induced NF-kappaB pathway and RhoA activation. Both KiSS1 overexpression and KP10 (kisspeptin-10) stimulation inhibited TNFalpha-induced NF-kappaB activity, suppressed TNFalpha-induced cell migration and cell attachment to fibronectin in breast cancer cells while KP10 has little effect on cancer cell proliferation. Furthermore, KP10 inhibited TNFalpha-induced cell migration and RhoA GTPase activation. Therefore, our data demonstrate that KiSS1 inhibits TNFalpha-induced NF-kappaB activation via downregulation of RhoA activation and suppression of breast cancer cell migration and invasion. (c) 2009 Wiley-Liss, Inc.