Abstract 2341: The Subtilisin-like proprotein convertases blockade inhibits the invasiveness of human primary melanoma with altered P53, CDKN2A and N-Ras genes

Abstract

Abstract Altered tumor suppressor p53 and/or CDKN2A as well as the Ras genes are frequently found in primary and metastatic melanomas. These alterations are responsible for the invasive/metastatic potential acquisition through their defective regulatory control on various MMPs and urokinase genes. Using primary human melanoma M10 cells with altered P53, CDKN2A and N-Ras genes, we found that inhibition of the proprotein convertases (PCs), enzymes involved in the proteolytic activation and/or expression of various cancer-related protein precursors reduced significantly their invasiveness. Analysis of M10 cells and their gastric and ganglion derived metastatic lesions revealed the presence of all the PCs found in the secretory pathway namely Furin, PACE4, PC5 and PC7. Expression of the general PCs inhibitor α1-PDX in these cells in a stable manner (M10/PDX) had no effect on the mRNA expression levels of these PCs. In vitro digestion assays and cell transfection experiments, revealed that M10/PDX cells present reduced PCs activity and are unable to process the PCs substrates proIGF-1R and proPDGF-A. These cells showed reduced migration, and invasion of Matrigel in vitro that paralleled decreased gelatinase MMP-2 activity and increased mRNA expression of tissue inhibitor of metalloproteinase 1 (TIMP-1) and TIMP-2. Furthermore, these cells showed decreased mRNA levels of urokinase-type plasminogen activator receptor (uPAR) and increased mRNA levels of plasminogen activator inhibitor-1 (PAI-1). Taken together, these data suggest that PCs activity inhibition has the ability to interfere with primary human melanoma cells invasiveness despite their altered P53, CDKN2A and N-Ras genes, suggesting the potential use of PCs as new therapeutic targets in melanoma. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2341.