Protease-Activated Receptors, Apoptosis and Tumor Growth

Abstract

Protease-activated receptors (PARs) are G-protein-coupled receptors (GPCRs) that are activated by a unique proteolytic mechanism. Besides the important role of blood coagulation factors in preventing bleeding after vascular injury, these serine proteinases actively engage target cells thereby fulfilling critical functions in cell biology. Cellular responses triggered by coagulation factor-induced PAR activation suggest that PARs play an important role in proliferation, survival and/or malignant transformation of tumor cells. Indeed, PAR expression correlates with cancer malignancy and clinical studies show that anticoagulant treatment is beneficial in cancer patients. In this review, we provide an overview on the PAR family, their mode of activation and mechanisms by which PAR signaling is terminated. In addition, we discuss the relationship between blood coagulation and cancer biology focusing on the potential role of PAR-induced modulation of cell survival, apoptosis and tumor growth.

Inhibition of the Plasma-Membrane-Associated Serine Protease Cathepsin G by Mycobacterium tuberculosis Rv3364c Suppresses Caspase-1 and Pyroptosis in Macrophages

“…PAR4 is considered an effective mediator of platelet activation and inflammation (Ramachandran et al, 2007). Alternatively, PAR receptors have been shown to modulate the program cell death (Borensztajn and Spek, 2008). To investigate the possible mechanism by which the inhibition of cathepsin G by M. tuberculosis wild-type inhibited activation of caspase-1, we examined the PAR4 protein expression levels in wild-type and 20A11 mutant infected cells (Figure 7).…”

Dabigatran Potentiates Gemcitabine-Induced Growth Inhibition of Pancreatic Cancer in Mice

“…Finally, one could argue that the observed difference between stromal PAR-1 deficiency and dabigatran treatment could be due to the fact that dabigatran also targets thrombin-induced effects on tumor cells. However, thrombin is mainly considered a driver of tumor cell proliferation (43) and, in the setting of pancreatic cancer, enhances the adhesion of pancreatic cancer cells to the extracellular matrix and/or endothelium (14).…”

Design, synthesis and biological evaluation of new peptide-based ureas and thioureas as potential antagonists of the thrombin receptor PAR1

“…In addition to the key role of thrombin in the blood coagulation cascade [1], this serine protease regulates multiple effects on an increasing variety of cells, such as: platelets [2,3], endothelial and smooth muscle cells [2,4], neurons and astrocytes in the nervous system [2,[4][5][6][7], immune and inflammatory cells [8,9], osteoblasts [10], and tumor cells [11][12][13][14]. These cellular effects are mainly mediated by the activation of the protease-activated receptor PAR1 [15].…”