Activation of human meprin-α in a cell culture model of colorectal cancer is triggered by the plasminogen-activating system

Abstract

The activation of latent proenzymes is an important mechanism for the regulation of localized proteolytic activity. Human meprin-α, an astacin-like zinc metalloprotease expressed in normal colon epithelial cells, is secreted as a zymogen into the intestinal lumen. Here, meprin is activated after propeptide cleavage by trypsin. In contrast, colorectal cancer cells secrete meprin-α in a non-polarized way, leading to accumulation and increased activity of meprin-α in the tumor stroma. We have analyzed the activation mechanism of promeprin-α in colorectal cancer using a co-culture model of the intestinal mucosa composed of colorectal adenocarcinoma cells (Caco-2) cultivated on filter supports and intestinal fibroblasts grown in the companion dish. We provide evidence that meprin-α is activated by plasmin and show that the presence of plasminogen in the basolateral compartment of the co-cultures is sufficient for promeprin-a activation. Analysis of the plasminogen-activating system in the co-cultures revealed that plasminogen activators produced and secreted by fibroblasts converted plasminogen to active plasmin, which in turn generated active meprin-α. This activation mechanism offers an explanation for the observed meprin-α activity in the tumor stroma, a prerequisite for a potential role of this protease in colorectal cancer.