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-alpha 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)-alpha-, interleukin (IL)-1 beta-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-alpha-, IL-1 beta- (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.