E-Cadherin Downregulation by Cathepsin L Plays a Role in the Proliferation of Insulin-Producing Cells following Inhibition of Serpin B13

Abstract

Experimental targeting of the exocrine pancreatic ductal tree stimulates beta-cell rejuvenation thereby underscoring the importance of functional crosstalk between the exocrine and endocrine pancreas. We recently found that antibody directed against serpin B13, a protease inhibitor expressed in the ductal epithelium of the exocrine pancreas, increased the catalytic activity of it’s protease target, cathepsin L (CatL) and subsequently upregulated Reg-mediated cellular proliferation in the islets. However, the exact molecular events that link catL activity to upregulated Reg and islet cell proliferation remain unclear. As increased E-cadherin levels during islet formation mediate a decline in beta-cell proliferation, and Reg upregulation has been linked to activation of beta-catenin, we hypothesized that the functional crosstalk between pancreatic ductal epithelium and the islets may involve CatL-mediated activation of the E-cadherin/β-catenin pathway. In support of this we found that E-cadherin was downregulated with a concomitant increase in Reg1 in mice treated with serpin B13 monoclonal antibody (mAb). Likewise, exposure to recombinant CatL or ductal epithelium extract treated with serpin B13 mAb caused decreased E-cadherin expression in the pancreatic islets during in vitro culture. On the other hand, this expression was recovered with CatL inhibitor. Moreover, treatment of MIN-6 insulinoma cells with ductal epithelium extract and serpin B13 mAb stimulated intranuclear accumulation of β-catenin, while Reg gene expression in the islets was markedly reduced in the presence of the β-catenin chemical inhibitor, FH535. These data establish E-cadherin as a potential target of CatL in the regulation of islet cell proliferation by an immunological response to serpin B13, and implicate the E-cadherin/β-catenin pathway as an islet sensing mechanism of the signals that are generated in the pancreatic exocrine milieu. Disclosure C. Lo: None. T. Sheu: None. J. Czyzyk: None.