Protease-activated receptor-1 (PAR-1) promotes the motility of human melanomas and is associated to their metastatic phenotype

Abstract

Protease-activated receptor-1 (PAR-1) is a unique G-protein-coupled receptor belonging to the protease-activated receptor family. Its activation leads to downstream signaling events that launch a variety of cellular responses related to tumor progression. PAR-1 expression has been associated to a variety of human cancers, and our previous studies reveal a high PAR-1 expression in melanoma specimens as compared to common nevi. In the present study, we investigated the contribution of PAR-1 to the malignant phenotype of human melanoma cell lines obtained from cutaneous primary lesions, capable of different metastatic behaviors in the patients from which they have been derived. We found that melanoma cells isolated from lesions giving rise to metastases in patients (WM115, WM278A, WM1361A, WM983A), had higher PAR-1 mRNA and protein expression, as compared to those obtained from lesions that did not develop metastatic disease (WM793, WM35). The cells isolated from metastatic primary lesions were able to colonize the lungs of immunodeficient SCID mice while those isolated from non-metastatic lesions were not. Additionally, cells expressing elevated PAR-1 had higher migratory and invasive abilities than those holding minimal PAR-1 expression. The migration and invasion capabilities of the melanoma cells expressing high PAR-1 were hampered by genetic and pharmacological interventions. The reduction of PAR-1 expression by siRNA and the inhibition of PAR-1 function by the SCH79797 specific antagonist significantly decreased the melanoma cell motility and invasiveness, down to an extent similar to that of the non-metastatic and low PAR-1 expressing cells. Our results provide strong evidence supporting the implication of PAR-1 in the malignant progression of human melanoma.

MDA-9/Syntenin Is Essential for Factor VIIa-induced Signaling, Migration, and Metastasis in Melanoma Cells

“…10B). The link established in this study between the TF signaling complex and MDA-9/syntenin has significant implications for the regulation of motility events associated with wound healing and tumor metastasis because PAR-1 has protumorigenic and pro-metastatic effects on cancer cells (52,53). In these contexts, up-regulation of an important PDZ scaffolding signaling protein, such as MDA-9/syntenin, through a TFdependent mechanism, with the ability to recruit and organize formation of the TF signaling complexes may significantly affect melanoma progression and potentially progression of other malignant tumors.…”

Kallikrein 6 is a novel molecular trigger of reactive astrogliosis

“…The involvement of PAR1 in KLK6-mediated changes in astrocyte stellation was examined using a PAR1-specific inhibitor, SCH79797 (35 nM, Tocris). SCH79797 is a selective non-peptide antagonist of PAR1 that has demonstrated specificity IN VITRO in a wide variety of cell types including, mouse kidney cells (Hocherl et al, 2011), a mouse motoneuron cell line (Vandell et al, 2008), rat primary astrocytes (Wang et al, 2006) and gingival fibroblasts (Ohuchi et al, 2011), as well as human melanoma (Silini et al, 2011) and cytotrophoblast cells (Grisaru-Granovsky et al, 2009). The role of PKC signaling was examined using a PKC specific inhibitor (Go6983, 60 nM, Tocris).…”

Targeting PAR1: Now What?

“…Since that time, PAR1 has been shown to participate in several aspects of malignancy including angiogenesis, tumor invasiveness, metastases and migration. Pharmacological inhibition or genetic deletion of PAR1 blocks growth of several cancer types in culture and impairs progression of several tumor types in mice, including lung cancer [48], melanoma [77], colon cancer [78] and pancreatic cancer [79]. Breast cancer has been most actively studied.…”