The protein phosphatase-2A subunit PR130 is linked to cytotoxic protein aggregate formation in mesenchymal pancreatic ductal adenocarcinoma cells

Protein phosphatase-2A (PP2A) is a major source of cellular serine/threonine phosphatase activity. PP2A B-type subunits regulate the cellular localization and activity of catalytically active PP2A-A/PP2A-C complexes towards individual PP2A targets. Despite ample knowledge on PP2A, there is limited knowledge on how PP2A B-type subunits regulate specific cellular functions. We show that mesenchymal pancreatic ductal adenocarcinoma (PDAC) cells have significantly higher expression levels of the PP2A B-type subunit PR130/PPP2R3A than epithelial PDAC cells. The higher levels of PR130 are linked to a cell-type selective vulnerability of mesenchymal PDAC cells to the PP2A inhibitor phendione. Phendione induces apoptosis and an accumulation of cytotoxic protein aggregates in such cells. Proteomic analyses reveal a specific upregulation of the chaperone heat shock protein HSP70 by phendione in mesenchymal PDAC cells. Inhibition of HSP70 promotes phendione-induced tumor cell death. We additionally disclose that phendione promotes a proteasomal degradation of PR130 in mesenchymal PDAC cells. Genetic elimination of PR130 sensitizes such cells to phendione-induced apoptosis and protein aggregate formation. These data illustrate pharmacologically amenable, selective dependencies of mesenchymal PDAC cells on PP2A-PR130 and HSP70. PP2A inhibitors trigger a harmful accumulation of protein aggregates in neurons. We provide evidence on how this can be exploited to kill mesenchymal tumor cells.