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Nutlin-3a Induces Cytoskeletal Rearrangement and Inhibits the Migration and Invasion Capacity of p53 Wild-Type Cancer Cells
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Abstract
MDM2 is an E3 ubiquitin ligase that binds and ubiquitinates the tumor suppressor protein p53, leading to its proteasomal degradation. Nutlin-3a (Nutlin) is a preclinical drug that binds MDM2 and prevents the interaction between MDM2 and p53, leading to p53 stabilization and activation of p53 signaling events. Previous studies have reported that Nutlin promotes growth arrest and/or apoptosis in cancer cells that express wild-type p53. In the current study, Nutlin treatment caused a cytoskeletal rearrangement in p53 wild-type human cancer cells from multiple etiologies. Specifically, Nutlin decreased actin stress fibers and reduced the size and number of focal adhesions in treated cells. This process was dependent on p53 expression but was independent of p21 expression and growth arrest. Consistent with this, Nutlin-treated cells failed to form filamentous actin-based motility structures (lamellipodia) and displayed significantly decreased directional persistence in response to migratory cues. Finally, chemotactic assays showed a p53-dependent/p21-independent decrease in migratory and invasive capacity of Nutlin-treated cells. Taken together, these findings reveal that Nutlin treatment can inhibit the migration and invasion capacity of p53 wild-type cells, adding to the potential therapeutic benefit of Nutlin and other small molecule MDM2 inhibitors. Mol Cancer Ther; 9(4); 895-905. (c)2010 AACR.
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Nutlin3a can inhibit migration and invasion via cytoskeletal changes in other cell types.
“others have demonstrated that nutlin3a can inhibit migration and invasion via changes in the cytoskeleton in other cell types.25”
From Combination therapy in a xenograft model of glioblastoma: Enhancement of the antitumor activity of temozolomide by an MDM2 antagonist (2017) · cites this paper as [25]
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Metadata
- Authors
- Moran, D. M., & Maki, C. G.
- Affiliations
- Rush University Medical Center (US)
- University of Chicago (US)
- Corresponding author
- Maki, Carl G.
- Venue
- Molecular Cancer Therapeutics
- Published
- 2010-04-01
- Volume
- 9
- Issue
- 4
- Pages
- 895-905
- ISSN
- 1535-7163 (ISSN-L)
- 1538-8514
- PMC
- PMC3075611
- OpenAlex
- W2108680269
- Cited by
- 35
- References
- 38
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 3 · 2023: 2 · 2022: 1 · 2021: 4 · 2020: 1 · 2018: 1 · 2017: 2 · 2016: 4 · 2015: 4 · 2013: 2 · 2012: 2
- FWCI
- 1.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Cancer Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5r01ca137598-05)
- National Cancer Institute (R01CA108843, R01 CA137598, 1R01CA137598-01A1)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Keywords
- Nutlin-3a, MDM2 inhibitors, cytoskeletal rearrangement, stress fibers, focal adhesions, cell migration, cell invasion, chemotaxis, p53-MDM2 interaction
- MeSH terms
- Actins, Cell Movement, Cytoskeleton, Humans, Imidazoles, Neoplasm Invasiveness, Piperazines, Pseudopodia, Tumor Suppressor Protein p53, Focal Adhesions, Stress Fibers, Cell Line, Tumor, Cyclin-Dependent Kinase Inhibitor p21
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