Reactivation of p53 by a Cytoskeletal Sensor to Control the Balance Between DNA Damage and Tumor Dissemination

Abnormal cell migration and invasion underlie metastasis, and actomyosin contractility is a key regulator of tumor invasion. The links between cancer migratory behavior and DNA damage are poorly understood. Using 3D collagen systems to recapitulate melanoma extracellular matrix, we analyzed the rela...

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Bibliographic Details
Published in:JNCI : Journal of the National Cancer Institute 2016-01, Vol.108 (1), p.djv289
Main Authors: Herraiz, Cecilia, Calvo, Fernando, Pandya, Pahini, Cantelli, Gaia, Rodriguez-Hernandez, Irene, Orgaz, Jose L, Kang, NaRa, Chu, Tinghine, Sahai, Erik, Sanz-Moreno, Victoria
Format: Article
Language:English
Subjects:
Actomyosin
Animals
Cell Line, Tumor
Cytoskeleton - metabolism
Cytoskeleton - pathology
DNA Damage - genetics
DNA Repair - genetics
Gene Expression Regulation, Neoplastic
Humans
Immunohistochemistry
Intracellular Signaling Peptides and Proteins - genetics
Melanoma - genetics
Melanoma - metabolism
Mice
Microscopy, Confocal
Microscopy, Fluorescence
Oxidative Stress
Protein Array Analysis
Proto-Oncogene Proteins - genetics
Reactive Oxygen Species - metabolism
rho-Associated Kinases - metabolism
Tissue Array Analysis
Tumor Suppressor Protein p53 - genetics
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Summary:Abnormal cell migration and invasion underlie metastasis, and actomyosin contractility is a key regulator of tumor invasion. The links between cancer migratory behavior and DNA damage are poorly understood. Using 3D collagen systems to recapitulate melanoma extracellular matrix, we analyzed the relationship between the actomyosin cytoskeleton of migrating cells and DNA damage. We used multiple melanoma cell lines and microarray analysis to study changes in gene expression and in vivo intravital imaging (n = 7 mice per condition) to understand how DNA damage impacts invasive behavior. We used Protein Tissue Microarrays (n = 164 melanomas) and patient databases (n = 354 melanoma samples) to investigate the associations between markers of DNA damage and actomyosin cytoskeletal features. Data were analyzed with Student's and multiple t tests, Mann-Whitney's test, one-way analysis of variance, and Pearson correlation. All statistical tests were two-sided. Melanoma cells with low levels of Rho-ROCK-driven actomyosin are subjected to oxidative stress-dependent DNA damage and ATM-mediated p53 protein stabilization. This results in a specific transcriptional signature enriched in DNA damage/oxidative stress responsive genes, including Tumor Protein p53 Inducible Protein 3 (TP53I3 or PIG3). PIG3, which functions in DNA damage repair, uses an unexpected catalytic mechanism to suppress Rho-ROCK activity and impair tumor invasion in vivo. This regulation was suppressed by antioxidants. Furthermore, PIG3 levels decreased while ROCK1/2 levels increased in human metastatic melanomas (ROCK1 vs PIG3; r = -0.2261, P < .0001; ROCK2 vs PIG3: r = -0.1381, P = .0093). The results suggest using Rho-kinase inhibitors to reactivate the p53-PIG3 axis as a novel therapeutic strategy; we suggest that the use of antioxidants in melanoma should be very carefully evaluated.
ISSN:0027-8874
1460-2105
DOI:10.1093/jnci/djv289