Influence of Endoplasmic Reticulum Stress on Urokinase Plasminogen Activation

The urokinase plasminogen activator or urokinase is a highly specific extracellular protease involved in numerous physiological and pathological processes. Its activity is a consequence of its interplay with its inhibitor, PAI1, and receptor, uPAR, and is finely regulated at several levels. The aim of the work was to investigate whether endoplasmic reticulum stress can modulate urokinase activity. Two tumor cell lines grown in cell culture were treated with Thapsigargin and sodium salicylate, inducers of ER stress response. Urokinase activity was determined in the conditioned media, and expression of uPA system molecules and molecules involved in response to ER stress in cell lysates was measured. ER stress influenced urokinase activity: while in the glioblastoma line its activity was increased, in breast cancer cells it was decreased. Differences in activity were a consequence of urokinase and PAI1 expression at the protein and RNA level. However, ER stress decreased cell migration, invasion, and proliferation regardless of the changes in urokinase activity. Gene expression analysis indicated that cell specific activation of some transcription factors and pathways could be responsible for different urokinase activity regulation.