Kisspeptin-10, a KISS1-derived decapeptide, inhibits tumor angiogenesis by suppressing Sp1-mediated VEGF expression and FAK/Rho GTPase activation.
Kisspeptin-10, a KISS1-derived decapeptide, inhibits tumor angiogenesis by suppressing Sp1-mediated VEGF expression and FAK/Rho GTPase activation.
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DOI：
10.1158/0008-5472.can-09-0476
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发表时间：
2009-09-01
期刊：
影响因子：
11.2
通讯作者：
Liu M
中科院分区：
文献类型：
--
作者：
Cho SG;Yi Z;Pang X;Yi T;Wang Y;Luo J;Wu Z;Li D;Liu M
Kisspeptin-10（Kp-10）是由KISS 1基因的初级翻译产物产生的一种十肽，是青春期发育的关键激素，通过激活G蛋白偶联受体54（Gpr 54）而抑制肿瘤转移。然而，Kp-10是否抑制血管生成，这对肿瘤生长和转移以及其他人类疾病至关重要，仍然是未知的。在这里，我们证明，Kp-10显着抑制人脐静脉内皮细胞（HUEVC）的迁移，侵袭，和管形成，血管生成的关键过程。利用鸡胚绒毛尿囊膜（CAM）试验和VEGF诱导的小鼠角膜微囊试验，我们证明了Kp-10抑制体内血管生成。此外，Kp-10通过抑制肿瘤血管生成来抑制人前列腺癌细胞（PC-3）异种移植的SCID小鼠中的肿瘤生长，而Kp-10对HUVECs和人前列腺癌细胞的增殖几乎没有影响。在解释潜在的分子机制中，我们证明Kp-10通过抑制Sp1与VEGF启动子的结合以及通过阻断c-Src/FAK和Rac/Cdc 42信号通路在HUVECs中的激活来抑制VEGF表达，从而导致肿瘤血管生成的抑制。
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.