Selective inhibition of proprotein convertases represses the metastatic potential of human colorectal tumor cells

Abstract

The proprotein convertases (PCs) are implicated in the activation of various precursor proteins that play an important role in tumor cell metastasis. Here, we report their involvement in the regulation of the metastatic potential of colorectal tumor cells. PC function in the human and murine colon carcinoma cell lines HT-29 and CT-26, respectively, was inhibited using siRNA targeting the PCs furin, PACE4, PC5, and PC7 or by overexpression of the general PC inhibitor α1-antitrypsin Portland (α1-PDX). We found that overexpression of α1-PDX and knockdown of furin expression inhibited processing of IGF-1 receptor and its subsequent activation by IGF-1 to induce IRS-1 and Akt phosphorylation, all important in colon carcinoma metastasis. These data suggest that the PC furin is a major IGF-1 receptor convertase. Expression of α1-PDX reduced the production of TNF-α and IL-1α by human colon carcinoma cells, and incubation of murine liver endothelial cells with conditioned media derived from these cells failed to induce tumor cell adhesion to activated murine endothelial cells, a critical step in metastatic invasion. Furthermore, colon carcinoma cells in which PC activity was inhibited by overexpression of α1-PDX when injected into the portal vein of mice showed a significantly reduced ability to form liver metastases. This suggests that inhibition of PCs is a potentially promising strategy for the prevention of colorectal liver metastasis.

Post-Endoplasmic Reticulum Rescue of Unstable MHC Class I Requires Proprotein Convertase PC7

“…This should be considerd when pPC inhibitors are used in the context of cancer therapies as suggested by several laboratories, based on findings that pPCs promote tumor growth and metastasis (52). However, we note that PC7 could also protect tumors from NK cell-mediated attack by securing high MHC I levels despite low TAP or tapasin function in malignant cells.…”

Interaction of the coiled‐coil domain with glycosaminoglycans protects angiopoietin‐like 4 from proteolysis and regulates its antiangiogenic activity

“…Members of the proprotein convertase family, including furin, cleave various proteins at RXKR, RXRR, RR, and KR sequences (23). HUVECs were cotransfected with plasmids encoding ANGPTL4 and ␣1-anti-trypsin Portland (␣1-PDX), a potent inhibitor of all proprotein convertases (24). We demonstrated that ␣1-PDX was efficiently transfected (green fluorescent protein expression from pIRES2-EGFP plasmid encoding ␣1-PDX; data not shown).…”

The renin–angiotensin system in the breast and breast cancer

“…The primary mechanism for prorenin activation has been considered to be through cleavage by prohormone convertases (Benjannet et al 1992), which may be highly expressed in cancer, including breast tumours, and this is associated with greater oestrogen dependency (Cheng et al 1997(Cheng et al , 2001). Of course, prohormone convertases may be involved in tumorigenic processes that do not involve either prorenin or angiotensin II (Siegfried et al 2003, Scamuffa et al 2008. Alternatively, the discovery of a specific prorenin receptor that binds prorenin and activates intracellular signalling pathways while at the same time activating its enzymic activity in the absence of cleavage opens new possibilities (Nguyen & Contrepas 2008, Nguyen 2011.…”