Kisspeptin-10 a KISS1-Derived Decapeptide Inhibits Tumor Angiogenesis by Suppressing Sp1-mediated VEGF Expression and FAK/Rho GTPase Activation

摘要

Kisspeptin-10 (Kp-10), a decapeptide derived from the primary translation product of KISS1 gene, has been previously reported to be a key hormone for puberty and an inhibitor for tumor metastasis via the activation of G protein-coupled receptor 54 (Gpr54). However, whether Kp-10 inhibits angiogenesis, which is critical for tumor growth and metastasis and other human diseases, is still unknown. Here we demonstrate that Kp-10 significantly inhibits human umbilical vein endothelial cell (HUEVC) migration, invasion, and tube formation, key processes in angiogenesis. Using chicken chorioallantoic membrane (CAM) assay and VEGF-induced mouse corneal micropocket assay, we demonstrate that Kp-10 inhibits angiogenesis in vivo. Furthermore, Kp-10 inhibits tumor growth in SCID mice xenografted with human prostate cancer cells (PC-3) through inhibiting tumor angiogenesis while Kp-10 has little effect on the proliferation of HUVECs and human prostate cancer cells. In deciphering the underlying molecular mechanisms, we demonstrate that Kp-10 suppresses VEGF expression by inhibiting the binding of Sp1 to VEGF promoter and by blocking the activation of c-Src/FAK and Rac/Cdc42 signaling pathway in HUVECs, leading to the inhibition of tumor angiogenesis.