Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher St. 67, 55131, Mainz, Germany.
Department of Zoology, Faculty of Science, Aswan University, Aswan, Egypt.
Cell Commun Signal. 2024 Apr 3;22(1):217. doi: 10.1186/s12964-024-01597-8.
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 responses of murine and human mesenchymal and epithelial PDAC cells to the specific PP2A inhibitor phendione. We assessed protein levels by immunoblot and proteomics and cell fate by flow cytometry, confocal microscopy, and genetic manipulation. We show that murine mesenchymal PDAC cells express significantly higher levels of the PP2A B-type subunit PR130 than epithelial PDAC cells. This overexpression of PR130 is associated with a dependency of such metastasis-prone cells on the catalytic activity of PP2A. Phendione induces apoptosis and an accumulation of cytotoxic protein aggregates in murine mesenchymal and human PDAC cells. These processes occur independently of the frequently mutated tumor suppressor p53. Proteomic analyses reveal that phendione upregulates the chaperone HSP70 in mesenchymal PDAC cells. Inhibition of HSP70 promotes phendione-induced apoptosis and phendione promotes a proteasomal degradation of PR130. Genetic elimination of PR130 sensitizes murine and human PDAC cells to phendione-induced apoptosis and protein aggregate formation. These data suggest that the PP2A-PR130 complex dephosphorylates and thereby prevents the aggregation of proteins in tumor cells.
作为细胞丝氨酸和苏氨酸磷酸酶活性的主要来源，蛋白磷酸酶 2A（PP2A）调节着健康和疾病中的信号通路。PP2A 复合物由催化亚基、支架亚基和 B 型亚基组成。十七种 PP2A B 型亚基将 PP2A 复合物引导至特定的底物。目前尚不清楚 PP2A B 型亚基如何决定肿瘤细胞的生长和药物反应性。胰腺导管腺癌（PDAC）是一种预后不良的疾病。我们分析了鼠源和人源间充质和上皮 PDAC 细胞对特定的 PP2A 抑制剂苯并二酮的反应。我们通过免疫印迹和蛋白质组学评估蛋白质水平，通过流式细胞术、共聚焦显微镜和遗传操作评估细胞命运。我们发现，鼠源间充质 PDAC 细胞表达的 PP2A B 型亚基 PR130 水平明显高于上皮 PDAC 细胞。这种 PR130 的过表达与这种易转移细胞对 PP2A 催化活性的依赖性有关。苯并二酮诱导鼠源间充质和人源 PDAC 细胞凋亡和细胞毒性蛋白聚集体的积累。这些过程独立于经常发生突变的肿瘤抑制因子 p53。蛋白质组学分析显示，苯并二酮在上皮 PDAC 细胞中上调伴侣蛋白 HSP70。抑制 HSP70 可促进苯并二酮诱导的凋亡，而苯并二酮促进 PR130 的蛋白酶体降解。PR130 的基因消除可使鼠源和人源 PDAC 细胞对苯并二酮诱导的凋亡和蛋白聚集体形成敏感。这些数据表明，PP2A-PR130 复合物去磷酸化，从而防止肿瘤细胞中蛋白质的聚集。
