Dataset Information

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

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: F Butter

LAB HEAD: Falk Butter

PROVIDER: PXD044854 | Pride | 2024-05-22

REPOSITORIES: Pride

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			Action	DRS
	20210507_SFB1_FBU_FB_CollabKramer_8296_Hcon_Lpd_1.raw	Raw
	20210507_SFB1_FBU_FB_CollabKramer_8296_Hcon_Lpd_2.raw	Raw
	20210507_SFB1_FBU_FB_CollabKramer_8296_Hcon_Lpd_3.raw	Raw
	20210507_SFB1_FBU_FB_CollabKramer_8296_Hcon_Lpd_4.raw	Raw
	20210507_SFB1_FBU_FB_CollabKramer_S411_Hcon_Lpd_1.raw	Raw

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The protein phosphatase-2A subunit PR130 is involved in the formation of cytotoxic protein aggregates in pancreatic ductal adenocarcinoma cells.

Nguyen Alexandra A Mustafa Al-Hassan M AM Leydecker Alessa K AK Halilovic Melisa M Murr Janine J Butter Falk F Krämer Oliver H OH

Cell communication and signaling : CCS 20240403 1

As a major source of cellular serine and threonine phosphatase activity, protein phosphatase-2A (PP2A) modulates signaling pathways in health and disease. PP2A complexes consist of catalytic, scaffolding, and B-type subunits. Seventeen PP2A B-type subunits direct PP2A complexes to selected substrates. It is ill-defined how PP2A B-type subunits determine the growth and drug responsiveness of tumor cells. Pancreatic ductal adenocarcinoma (PDAC) is a disease with poor prognosis. We analyzed the res ...[more]

PMID: 38570831

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Project description:Protein phosphatase 2A (PP2A) is one of the most common serine/threonine phosphatases in mammalian cells and primarily functions to regulate cell signaling, glycolipid metabolism, and apoptosis. Its PP2A catalytic subunit (PP2Ac) plays an important role in its function. Nonetheless, at present, there are only a few reports on the regulatory role of PP2Ac in pancreatic β-cells under lipotoxicity. Mouse pancreatic insulinoma (MIN6) cells were transfected by lentiviruses to generate PP2Ac knockdown cells and incubated with palmitate (PA) to establish the lipotoxicity model. Serine/Threonine Phosphatase Assay System kit, Cell Counting Kit-8 (CCK-8), flow cytometry, enzyme-linked immunosorbent assay (ELISA), Western Blotting (WB) and other techniques were used to measure PP2A activity, cell viability, apoptosis, oxidative stress, and insulin secretion. An animal model of lipotoxicity with knockdown of PP2Ac was established by a high-fat diet (HFD) after using adeno-associated viruses (AAV) to interfere with PP2Ac expression in mouse pancreatic tissues. Serine/Threonine Phosphatase Assay System kit, ELISA, pancreatic tissue immunofluorescence and other techniques were used to measure PP2A activity in pancreatic tissue, serum insulin level and the proliferation of mouse pancreatic β-cells. We found that PP2Ac knockdown inhibited lipotoxicity-induced PP2A hyperactivation, increased the resistance of pancreatic β-cells to lipotoxicity, decreased PA-induced apoptosis in MIN6 cells, protected the function of both the endoplasmic reticulum (ER) and mitochondria, and improved insulin secretion. By mRNA sequencing and Western blotting analysis, we hypothesized that the protective effects of PP2Ac knockdown in MIN6 cells may be mediated by the MAPK pathway. Moreover, the results obtained from animal experiments suggest that the specific knockdown of pancreatic PP2Ac could effectively attenuate HFD-induced insulin resistance and reduce the compensatory proliferation of pancreatic β-cells in mice. The present study revealed the effects and mechanisms of interfering with PP2Ac gene expression on pancreatic β-cells in vivo and in vitro, which might provide insights for the treatment of type 2 diabetes in the clinic.