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

J Clin Invest. 2008 Jan;118(1):352-63. doi: 10.1172/JCI32040.

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 alpha1-antitrypsin Portland (alpha1-PDX). We found that overexpression of alpha1-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 alpha1-PDX reduced the production of TNF-alpha and IL-1alpha 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 alpha1-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Cell Adhesion / genetics
  • Cell Line, Tumor
  • Colorectal Neoplasms / enzymology*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / pathology
  • Colorectal Neoplasms / prevention & control
  • Humans
  • Insulin Receptor Substrate Proteins
  • Interleukin-1beta / biosynthesis
  • Interleukin-1beta / genetics
  • Liver Neoplasms / enzymology*
  • Liver Neoplasms / genetics
  • Liver Neoplasms / pathology
  • Liver Neoplasms / prevention & control
  • Liver Neoplasms / secondary
  • Mice
  • Neoplasm Metastasis
  • Proprotein Convertases / antagonists & inhibitors
  • Proprotein Convertases / genetics
  • Proprotein Convertases / metabolism*
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor, IGF Type 1 / genetics
  • Receptor, IGF Type 1 / metabolism*
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / genetics
  • alpha 1-Antitrypsin / biosynthesis*
  • alpha 1-Antitrypsin / genetics
  • alpha 1-Antitrypsin / pharmacology*

Substances

  • Adaptor Proteins, Signal Transducing
  • IRS1 protein, human
  • Insulin Receptor Substrate Proteins
  • Interleukin-1beta
  • Irs1 protein, mouse
  • Tumor Necrosis Factor-alpha
  • alpha 1-Antitrypsin
  • Receptor, IGF Type 1
  • Proto-Oncogene Proteins c-akt
  • Proprotein Convertases