| Reactivation of p53 by a Cytoskeletal Sensor to Control the Balance Between DNA Damage and Tumor Dissemination | | Reactivation of p53 by a Cytoskeletal Sensor to Control the Balance Between DNA Damage and Tumor Dissemination | Herraiz C, Calvo F, Pandya P, Cantelli G, Rodriguez-Hernandez I, Orgaz JL, Kang N, Chu T, Sahai E, Sanz-Moreno V | 2015-10-12T22:00:00Z | <p style="text-align:justify;"><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="color:#2a2a2a;font-weight:bold;background-color:#eff2f7;">Abstract</span></p><p style="text-align:justify;"><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2"><span style="color:#2a2a2a;font-weight:bold;background-color:#eff2f7;"></span><span style="font-style:inherit;font-weight:bold;color:#2a2a2a;background-color:#eff2f7;">Background:</span></span></p><section class="abstract ms-rteThemeFontFace-1 ms-rteFontSize-2" style="box-sizing:border-box;margin:0px;padding:0px 1.2rem 1.7rem;border:0px;font-stretch:inherit;line-height:inherit;vertical-align:baseline;background-color:#eff2f7;color:#2a2a2a;text-align:justify;"><section class="sec ms-rteThemeFontFace-1 ms-rteFontSize-2" style="box-sizing:border-box;margin:0px;padding:0px;border:0px;font-style:inherit;font-stretch:inherit;line-height:inherit;vertical-align:baseline;"><p style="box-sizing:border-box;margin-bottom:0px;padding:0px;border:0px;font-style:inherit;font-stretch:inherit;line-height:1.7em;vertical-align:baseline;">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.</p></section><section class="sec ms-rteThemeFontFace-1 ms-rteFontSize-2" style="box-sizing:border-box;margin:0px;padding:0px;border:0px;font-style:inherit;font-stretch:inherit;line-height:inherit;vertical-align:baseline;"><div class="title -title" style="box-sizing:border-box;margin:1rem 0px 0.6rem;padding:0px;border:0px;font-style:inherit;font-weight:bold;font-stretch:inherit;line-height:inherit;vertical-align:baseline;">Methods:</div><p style="box-sizing:border-box;margin-bottom:0px;padding:0px;border:0px;font-style:inherit;font-stretch:inherit;line-height:1.7em;vertical-align:baseline;"><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2">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 <span style="box-sizing:border-box;margin:0px;padding:0px;border:0px;font-style:italic;font-stretch:inherit;line-height:inherit;vertical-align:baseline;">t</span> tests, Mann-Whitney’s test, one-way analysis of variance, and Pearson correlation. All statistical tests were two-sided.</span></p></section><section class="sec ms-rteThemeFontFace-1 ms-rteFontSize-2" style="box-sizing:border-box;margin:0px;padding:0px;border:0px;font-style:inherit;font-stretch:inherit;line-height:inherit;vertical-align:baseline;"><div class="title -title" style="box-sizing:border-box;margin:1rem 0px 0.6rem;padding:0px;border:0px;font-style:inherit;font-weight:bold;font-stretch:inherit;line-height:inherit;vertical-align:baseline;">Results:</div><p style="box-sizing:border-box;margin-bottom:0px;padding:0px;border:0px;font-style:inherit;font-stretch:inherit;line-height:1.7em;vertical-align:baseline;"><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2">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; <span style="box-sizing:border-box;margin:0px;padding:0px;border:0px;font-style:italic;font-stretch:inherit;line-height:inherit;vertical-align:baseline;">r</span> = -0.2261, <span style="box-sizing:border-box;margin:0px;padding:0px;border:0px;font-style:italic;font-stretch:inherit;line-height:inherit;vertical-align:baseline;">P</span> < .0001; ROCK2 vs PIG3: <span style="box-sizing:border-box;margin:0px;padding:0px;border:0px;font-style:italic;font-stretch:inherit;line-height:inherit;vertical-align:baseline;">r</span> = -0.1381, <span style="box-sizing:border-box;margin:0px;padding:0px;border:0px;font-style:italic;font-stretch:inherit;line-height:inherit;vertical-align:baseline;">P</span> = .0093).</span></p></section><section class="sec ms-rteThemeFontFace-1 ms-rteFontSize-2" style="box-sizing:border-box;margin:0px;padding:0px;border:0px;font-style:inherit;font-stretch:inherit;line-height:inherit;vertical-align:baseline;"><div class="title -title" style="box-sizing:border-box;margin:1rem 0px 0.6rem;padding:0px;border:0px;font-style:inherit;font-weight:bold;font-stretch:inherit;line-height:inherit;vertical-align:baseline;">Conclusions:</div><p style="box-sizing:border-box;margin-bottom:0px;padding:0px;border:0px;font-style:inherit;font-stretch:inherit;line-height:1.7em;vertical-align:baseline;">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.</p></section></section><p><br></p> | <p><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2"><strong>Journal of National Cancer Institute.</strong><strong> </strong>108(1): djv289. <br></span></p><p><a href="https://doi.org/10.1093/jnci/djv289"><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2">https://doi.org/10.1093/jnci/djv289</span></a><br></p> | 184 | | |
