Tan K, Cho S-G, Luo W, Yi T, Wu X, Siwko S, Liu M, Yuan W
College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, P.R. China.
Curr Mol Med. 2014;14(5):652-62. doi: 10.2174/1566524014666140603115314.
The metastasis suppressor protein Kisspeptin regulates cancer cell proliferation and motility through its receptor, GRP54. However, the critical downstream effectors remain unclear. In this study, we investigated GPR54 signaling in breast cancer cells. Kisspeptin stimulation caused a decrease in migration of multiple breast cancer cell lines. Also, Kisspeptin inhibited MDA-MB-231 cell colony formation in 3D matrigel culture and in soft agar. Kisspeptin treatment elevated phosphorylated PKD1 in a PKC-dependent manner. However, knockdown of either GPR54 or PKD1 increased breast cancer cell migration and invasion. Furthermore, GPR54 knockdown blocked Kisspeptin-induced phosphorylation of PKD1. Finally, Kisspeptin stimulation induced a PKD1 phosphorylation-dependent decrease in expression of Slug, a transcription factor that drives epithelial-mesenchymal transition (EMT), and a concomitant increase in E-cadherin expression. Therefore, KiSS1/GPR54 signaling through PKD1 acts to maintain the epithelial state and to inhibit breast cancer cell invasiveness, and exerts functions associated with its role as a metastasis suppressor.
转移抑制蛋白亲吻素通过其受体GPR54调节癌细胞的增殖和迁移。然而，关键的下游效应器仍不清楚。在本研究中，我们调查了乳腺癌细胞中的GPR54信号传导。亲吻素刺激导致多种乳腺癌细胞系的迁移减少。此外，亲吻素在三维基质胶培养和软琼脂中抑制MDA-MB-231细胞集落形成。亲吻素处理以PKC依赖的方式提高了磷酸化的PKD1水平。然而，敲低GPR54或PKD1均增加了乳腺癌细胞的迁移和侵袭。此外，敲低GPR54可阻断亲吻素诱导的PKD1磷酸化。最后，亲吻素刺激诱导了驱动上皮-间质转化（EMT）的转录因子Slug表达的PKD1磷酸化依赖性降低，并伴随E-钙黏蛋白表达增加。因此，通过PKD1的KiSS1/GPR54信号传导作用于维持上皮状态并抑制乳腺癌细胞侵袭，并发挥与其作为转移抑制因子的作用相关的功能。
