title: Crosstalk between protease-activated receptor 1 and platelet-activating factor receptor regulates melanoma cell adhesion molecule (MCAM/MUC18) expression and melanoma metastasis.
abstract: The cellular and molecular pathways that regulate platelet activation, blood coagulation, and inflammation are emerging as critical players in cancer progression and metastasis. Here, we demonstrate a novel signaling mechanism whereby protease-activated receptor 1 (PAR1) mediates expression of melanoma cell adhesion molecule MCAM/MUC18 (MUC18), a critical marker of melanoma metastasis, via activation of platelet-activating factor receptor (PAFR) and cAMP-responsive element-binding protein (CREB). We found that PAR1 silencing with small hairpin RNA inhibits MUC18 expression in metastatic melanoma cells by inhibiting CREB phosphorylation, activity, and binding to the MUC18 promoter. We further demonstrate that the PAF/PAFR pathway mediates MUC18 expression downstream of PAR1. Indeed, PAR1 silencing down-regulates PAFR expression and PAF production, PAFR silencing blocks MUC18 expression, and re-expression of PAFR in PAR1-silenced cells rescues MUC18 expression. We further demonstrate that the PAR1-PAFR-MUC18 pathway mediates melanoma cell adhesion to microvascular endothelial cells, transendothelial migration, and metastatic retention in the lungs. Rescuing PAFR expression in PAR1-silenced cells fully restores metastatic phenotype of melanoma, indicating that PAFR plays critical role in the molecular mechanism of PAR1 action. Our results link the two pro-inflammatory G-protein-coupled receptors, PAR1 and PAFR, with the metastatic dissemination of melanoma and suggest that PAR1, PAFR, and MUC18 are attractive therapeutic targets for preventing melanoma metastasis.
authors.affiliation: Department of Cancer Biology, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Vladislava O
authors.initials: VO
authors.lastname: Melnikova
authors.forename: Krishnakumar
authors.initials: K
authors.lastname: Balasubramanian
authors.forename: Gabriel J
authors.initials: GJ
authors.lastname: Villares
authors.forename: Andrey S
authors.initials: AS
authors.lastname: Dobroff
authors.forename: Maya
authors.initials: M
authors.lastname: Zigler
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.forename: Frederik
authors.initials: F
authors.lastname: Petersson
authors.forename: Janet E
authors.initials: JE
authors.lastname: Price
authors.forename: Alan
authors.initials: A
authors.lastname: Schroit
authors.forename: Victor G
authors.initials: VG
authors.lastname: Prieto
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.forename: Menashe
authors.initials: M
authors.lastname: Bar-Eli
mesh_terms: D051929:CD146 Antigen / Q000378:metabolism; D050882:CREB-Binding Protein / Q000378:metabolism; D045744:Cell Line, Tumor; D020868:Gene Silencing; D006801:Humans; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D009362:Neoplasm Metastasis; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D051929:CD146 Antigen; C497902:MCAM protein, human; D010980:Platelet Membrane Glycoproteins; D034741:RNA, Small Interfering; D044463:Receptor, PAR-1; D043562:Receptors, G-Protein-Coupled; D014157:Transcription Factors; C039351:platelet activating factor receptor; D050882:CREB-Binding Protein
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