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

被引:107
作者
Scamuffa, Nathalie [1 ,2 ]
Siegfried, Geraldine [3 ]
Bontemps, Yannick [1 ,2 ]
Ma, Liming [4 ]
Basak, Ajoy [4 ]
Cherel, Ghislaine [3 ]
Calvo, Fabien [1 ,2 ]
Seidah, Nabil G. [5 ]
Khatib, Abdel-Majid [1 ,2 ]
机构
[1] Inst Genet Mol, Equipe AVENIR, INSERM, Lab Pharmacol Expt & Clin,U716, F-75010 Paris, France
[2] Univ Paris 07, Paris, France
[3] Univ Paris Sud, Fac Med Paris Sud, INSERM,U770, IFR 93, F-94275 Le Kremlin Bicetre, France
[4] Ottawa Hlth Res Ctr, Reg Protein Chem Ctr, Ottawa, ON, Canada
[5] Clin Res Inst Montreal, Biochem Neuroendocrinol Lab, Montreal, PQ H2W 1R7, Canada
关键词
D O I
10.1172/JCI32040
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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 alpha 1-antitrypsin Portland (alpha 1-PDX). We found that overexpression of alpha 1-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 alpha 1-PDX reduced the production of TNF-alpha and IL-1 alpha 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 alpha 1-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.
引用
收藏
页码:352 / 363
页数:12
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