Paired Basic Amino Acid-cleaving Enzyme 4 (PCSK6): An Emerging New Target Molecule in Human Melanoma
Carsten Weishaupt, Arianna Mastrofrancesco, Dieter Metze, Björn Kemper, Agatha Stegemann, Mauro Picardo, Andres J.P. Klein-Szanto, Markus Böhm
Although recent therapeutic developments raise hope, melanoma remains a devastating disease with a need for new treatment targets. In other tumours prohormone convertases have been shown to be pro-tumourigenic as they are involved in processing preforms of matrix-metalloproteinases, growth factors and adhesion molecules. The aim of this study was to look for new treatment options for melanoma, by investigating the role of the prohormone convertase Paired basic Amino acid-Cleaving Enzyme 4 (PACE4/PCSK6) in melanoma cell lines and human melanoma tissue. PACE4-transfected A375 melanoma cells displayed significantly increased proliferation, MMP-2 production, gelatinase activity and migratory capacity in vitro compared with sham-transfected cells. In vivo, elevated PACE4 expression resulted in significantly increased tumour growth on immunodeficient mice. In the majority of 45 human primary melanomas and melanoma metastases ex vivo PACE4 immunoreactivity was detectable, while it was absent in in situ melanomas. These results indicate PACE4 as a regulator of melanoma cell aggressiveness.
Prohormone convertases are enzymes that are involved in regulating the activity of proteins, such as growth factors and adhesion molecules, which are important players in carcinogenesis. Metastatic melanoma is a devastating disease with an urgent need for new treatment options. This study investigated the role of the prohormone convertase PACE4 in melanoma. The results showed that the expression of PACE4 correlates with enhanced proliferation and migratory capacity in vitro and increased tumour growth in vivo. Unlike in situ melanomas it is expressed in advanced human melanomas. Thus, PACE4 is associated with melanoma aggressiveness and may serve as a novel target for melanoma treatment.