PME-1 modulates protein phosphatase 2A activity to promote the malignant phenotype of endometrial cancer cells
| Autor: | Ewa Wandzioch, Amy Werda, Sophie Bail, Michelle Pusey, Aishwarya Bhaskar, Lyndi M. Rice, Jing-Jing Yang, Mariya Nestor |
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| Rok vydání: | 2014 |
| Předmět: |
MAPK/ERK pathway
Cancer Research Protein subunit Phosphatase Mice Nude Cell Growth Processes Methylation Mice medicine Animals Humans Protein Phosphatase 2 Protein kinase B Cell growth Chemistry Endometrial cancer Protein phosphatase 2 medicine.disease Endometrial Neoplasms Phenotype Oncology Cancer research Heterografts Female Signal transduction Carboxylic Ester Hydrolases Signal Transduction |
| Zdroj: | Cancer research. 74(16) |
| ISSN: | 1538-7445 |
| Popis: | Protein phosphatase 2A (PP2A) negatively regulates tumorigenic signaling pathways, in part, by supporting the function of tumor suppressors like p53. The PP2A methylesterase PME-1 limits the activity of PP2A by demethylating its catalytic subunit. Here, we report the finding that PME-1 overexpression correlates with increased cell proliferation and invasive phenotypes in endometrial adenocarcinoma cells, where it helps maintain activated ERK and Akt by inhibiting PP2A. We obtained evidence that PME-1 could bind and regulate protein phosphatase 4 (PP4), a tumor-promoting protein, but not the related protein phosphatase 6 (PP6). When the PP2A, PP4, or PP6 catalytic subunits were overexpressed, inhibiting PME-1 was sufficient to limit cell proliferation. In clinical specimens of endometrial adenocarcinoma, PME-1 levels were increased and we found that PME-1 overexpression was sufficient to drive tumor growth in a xenograft model of the disease. Our findings identify PME-1 as a modifier of malignant development and suggest its candidacy as a diagnostic marker and as a therapeutic target in endometrial cancer. Cancer Res; 74(16); 4295–305. ©2014 AACR. |
| Databáze: | OpenAIRE |
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