Effect of aspirin on the Wnt/β-catenin pathway is mediated via protein phosphatase 2A
Abstract
Nonsteroidal anti-inflammatory drugs show chemopreventive efficacy in colon cancer, but the mechanism behind this remains unclear. Elucidating this mechanism is seen as vital to the development of new chemopreventive agents. We studied the effects of aspirin on the oncogenic Wnt/beta-catenin pathway activity in colorectal cancer cell lines and observed that aspirin dose-dependently decreased the activity of this pathway, as judged by TCF-driven luciferase activity, reduced Wnt target gene expression and increased phosphorylation of beta-catenin by immunoblotting. Furthermore, the ubiquitination and cytoplasmic levels of beta-catenin were assessed by immunoblotting, and also the localization of beta-catenin was shown by green fluorescent protein-tagged beta-catenin and time-lapse fluorescent imaging. Importantly, aspirin treatment caused increased phosphorylation of protein phosphatase 2A (PP2A), an event associated with inhibition of PP2A enzymatic activity, which was confirmed by a reduction in enzymatic PP2A activity. Moreover, this inhibition of PP2A enzymatic activity was essential for the effects of aspirin on the Wnt/beta-catenin pathway as shown by transient transfection with PP2A constructs. The findings in this article provide a molecular explanation for the efficacy of aspirin in chemoprevention of colorectal cancer and shows biochemical evidence that PP2A is an important regulator of Wnt/beta-catenin pathway activity in these cells.
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Tautomycin specifically inhibits PP1 without affecting PP2A, and okadaic acid efficiently inhibits PP2A.
“We determined the efficiency and specificity of these inhibitors by monitoring the level of Thr320 phosphorylation on the PP1 catalytic subunit α (p-PP1α) [24] and of Tyr307 phosphorylation on the PP2A catalytic subunit (p-PP2A) by immunoblotting with appropriate antibodies [25].”
From The Spi1/PU.1 transcription factor accelerates replication fork progression by increasing PP1 phosphatase in leukemia (2017) · cites this paper as [25]
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- Authors
- Bos, C. L., Kodach, L. L., van den Brink, G. R., Diks, S. H., van Santen, M. M., Richel, D. J., Peppelenbosch, M. P., & Hardwick, J. C. H.
- Affiliations
- University of Amsterdam (NL)
- University of Groningen (NL)
- Corresponding author
- Hardwick, J C H
- Venue
- Oncogene
- Published
- 2006-07-31
- Volume
- 25
- Issue
- 49
- Pages
- 6447-6456
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2153611464
- Cited by
- 156
- References
- 38
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 5 · 2023: 6 · 2022: 4 · 2021: 17 · 2020: 10 · 2019: 10 · 2018: 10 · 2017: 15 · 2016: 14 · 2015: 8 · 2014: 12 · 2013: 14 · 2012: 5
- FWCI
- 1.35
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Pharmacology › Inflammatory mediators and NSAID effects
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Keywords
- aspirin, Wnt/β-catenin signaling, protein phosphatase 2A, colorectal cancer chemoprevention, β-catenin phosphorylation, β-catenin ubiquitination, nonsteroidal anti-inflammatory drugs, colorectal cancer cell lines
- MeSH terms
- Anti-Inflammatory Agents, Non-Steroidal, Aspirin, Cytoplasm, Humans, Phosphoprotein Phosphatases, Phosphorylation, Protein Processing, Post-Translational, Tumor Cells, Cultured, Signal Transduction, Down-Regulation, Gene Expression Regulation, Neoplastic, Genes, Reporter, Ubiquitin, Ubiquitin-Protein Ligase Complexes, HCT116 Cells, Wnt Proteins, beta Catenin, TCF Transcription Factors, Protein Phosphatase 2, Anaphase-Promoting Complex-Cyclosome
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