The emerging role of the thrombin receptor (PAR-1) in melanoma metastasis--a possible therapeutic target

Abstract

Melanoma remains as the deadliest form of skin cancer with limited and inefficient treatment options available for patients with metastatic disease. Within the last decade, the thrombin receptor, Protease Activated Receptor-1, has been described as an essential gene involved in the progression of human melanoma. PAR-1 is known to activate adhesive, invasive and angiogenic factors to promote melanoma metastasis. It is overexpressed not only in metastatic melanoma cell lines but is also highly expressed in metastatic lesions as compared to primary nevi and normal skin. Recently, PAR-1 has been described to regulate the gap junction protein Connexin 43 and the tumor suppressor gene Maspin to promote the metastatic melanoma phenotype. Herein, we review the role of PAR-1 in the progression of melanoma as well as utilizing PAR-1-regulated genes as potential therapeutic targets for melanoma treatment.

Figure 1. Activation and signaling of PAR-1

Thrombin, the most potent activator of PAR-1, binds to the hirudin-like binding domain on the N-terminus of the receptor and proteolytically cleaves between Arg 41 and Ser 42 in an irreversible manner. Ser 42 now acts as a tethered ligand to activate PAR-1. PAR-1 signals through G-protein subtypes, Gα_q, Gα_i, and Gβγ to activate PKC and MAPK, inhibit adenylyl cyclase as well as activate PI3-K and PKB.

Figure 2. PAR-1 regulates Maspin expression in melanoma

Silencing PAR-1 results in decreased activation of p38 MAPK, a known inhibitor of CBP/p300. This results in higher levels of CBP/p300 HAT activity allowing for increased binding of c-Jun and Ets-1 transcription factors to the Maspin promoter. Increased Maspin expression further inhibits cell invasion, through decreased expression and activity of MMP-2, as well as angiogenesis through decreased VEGF expression.