µ‐Calpain promotes epithelial cell survival and adherens junction disruption during Helicobacter pylori infection

Abstract

H.pylori (Hp) is a risk factor for gastritis, gastric ulcers, and adenocarcinoma. The ability of Hp to disrupt intercellular adhesion and alter cell survival may influence the clinical outcome of infection. Calpain family proteases cleave the adherens junction (AJ) components E‐cadherin and β‐catenin, and modulate pathways regulating cell survival and apoptosis.AIMS1) to assess the effects of Hp on calpains 2) to assess the effects of calpains on Hp‐induced AJ defects and cell survival.RESULTSEpithelial (MKN45 and SCBN) monolayers were challenged for 24h with Hp strain SS1 or the human isolate 60190 in the presence or absence of calpain inhibitor PD150606. Immunoblotting revealed that Hp‐challenged monolayers displayed elevated levels of active µ‐calpain and the cleaved form of the calpain substrate α‐spectrin. Immunoblotting and immunostaining revealed calpain‐dependent, Hp‐induced E‐cadherin redistribution and cleavage of the 120kDa full‐length E‐cadherin to a functionally‐impaired 100kDa form. Also, Hp induced membrane‐to‐nucleus translocation of β‐catenin in a calpain dependent fashion. Finally, calpain inhibition enhanced Hp‐induced apoptosis, PARP cleavage, and caspase‐3 activation.CONCLUSIONHp‐induced activation of µ‐calpain mediates processes associated with tumorigenesis including AJ disruption and promotion of abnormal cell survival. Funded by CIHR.