Gastric cancer cell types display distinct proteasome/immunoproteasome patterns associated with migration and resistance to proteasome inhibitors

Gastric cancers (GC) display histological and molecular differences. This heterogeneity has limited the development of new therapeutic strategies which requires the identification of the molecular players involved in GC pathogenesis and the investigation of their responsiveness to drugs. Several proteasome subunits have been identified as prognostic markers in GC and their role studied by gene knockdown. However, proteasomes are multi-subunit protein complexes co-existing in multiple forms with distinct activity/specificity and ability to change in response to inhibitors. Information on the role of different proteasome particles in cancer and their relevance as therapeutic targets is limited.

Based on this evidence, subunit assembly into proteasome complexes and activity were investigated by native PAGE followed by immunoblotting, and by using fluorogenic substrates, respectively.

Here we show that GC cell lines with epithelial and/or diffuse Lauren's histotype express different levels of immunoproteasome subunits and equal amounts of constitutive counterparts. Immunoproteasome subunits were highly expressed and preferentially assembled into 19S capped complexes in diffuse-type cells, where most of the activity was catalyzed by the 26S and 30S particles. In epithelial cells, activity appeared equally distributed between 19S- and 11S-capped proteolytic particles. This proteasome pattern was associated with higher resistance of diffuse-type cells to proteasome inhibition. Immunoproteasome inhibition by ONX 0914 did not influence cell viability but affected metastatic cell migration.

These results suggest that pharmacological inhibition of the immunoproteasome may be useful in treating metastatic gastric cancers.