KiSS1-Induced GPR54 Signaling Inhibits Breast Cancer Cell Migration and Epithelial-Mesenchymal Transition via Protein Kinase D1
K. Tan, S.-G. Cho, W. Luo, T. Yi, X. Wu, S. Siwko, M. Liu and W. Yuan
Affiliation: College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, P.R. China.
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.
Keywords: Breast cancer, G protein coupled receptors (GPCR), GPR54, invasion, KiSS1, migration, protein kinase
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