title: Suppressive effects of dabrafenib on endothelial protein C receptor shedding.
abstract: Beyond its role in the activation of protein C, the endothelial cell protein C receptor (EPCR) plays an important role in the cytoprotective pathway. EPCR can be shed from the cell surface, which is mediated by tumor necrosis factor-α converting enzyme (TACE). Dabrafenib (DAB) is a B-Raf inhibitor and initially used for the treatment of metastatic melanoma therapy. However, little is known about the effects of DAB on EPCR shedding. We investigated this issue by monitoring the effects of DAB on phorbol-12-myristate 13-acetate (PMA)-, tumor necrosis factor (TNF)-α-, interleukin (IL)-1β-induced EPCR shedding in human umbilical vein endothelial cells (HUVECs), and cecal ligation and puncture (CLP)-mediated EPCR shedding in mice and underlying mechanism. Data demonstrate that DAB induced potent inhibition of PMA-, TNF-α-, IL-1β- (in HUVECs), and CLP-induced EPCR shedding (in mice) via inhibition of phosphorylation of mitogen-activated protein kinases (MAPKs) such as p38, janus kinase (JNK), and extracellular signal-regulated kinase (ERK) 1/2. DAB also inhibited the expression and activity of PMA-induced TACE in HUVECs suggesting that p38, ERK1/2, and JNK could be molecular targets of DAB. These results demonstrate the potential of DAB as an anti-EPCR shedding reagent against PMA-mediated and CLP-mediated EPCR shedding.
authors.affiliation: Department of Anatomy and Histology, College of Korean MedicineDaegu Haany University, Gyeongsan, 38610, Republic of Korea.
authors.forename: Sae-Kwang
authors.initials: SK
authors.lastname: Ku
authors.affiliation: Cancer Control Team, Gachon University Gil Medical Center, Incheon, 21565, Republic of Korea.
authors.forename: Jongdoo
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Herbal Formulation, MRC-GHF College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do, 38610, Republic of Korea.
authors.forename: Sang Chan
authors.initials: SC
authors.lastname: Kim
authors.affiliation: College of Pharmacy, CMRI Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, Kyungpook National University, Daegu, 41566, Republic of Korea. baejs@knu.ac.kr.|College of Pharmacy, Kyungpook National University, 80 Dahak-ro, Buk-gu, Daegu, 702-701, Republic of Korea. baejs@knu.ac.kr.
authors.forename: Jong-Sup
authors.initials: JS
authors.lastname: Bae
mesh_terms: D000072198:ADAM17 Protein / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D002478:Cells, Cultured; D015536:Down-Regulation; D058492:Drug Repositioning; D000074283:Endothelial Protein C Receptor; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010091:Oximes / Q000494:pharmacology*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D015703:Antigens, CD; D000074283:Endothelial Protein C Receptor; D007093:Imidazoles; D053583:Interleukin-1beta; D010091:Oximes; C478370:PROCR protein, human; D047428:Protein Kinase Inhibitors; D011956:Receptors, Cell Surface; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; D013755:Tetradecanoylphorbol Acetate; C561627:dabrafenib
keywords: CLP; Dabrafenib; EPCR shedding; Vascular inflammation