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Topical DNA oligonucleotide therapy reduces UV-induced mutations and photocarcinogenesis in hairless mice.

ABSTRACT: UV-induced DNA damage gives rise to mutations and skin cancer. We have previously reported that treatment of skin cells in vitro with thymidine dinucleotide (pTT) activates p53 and increases the ability of cells to repair subsequent UV-induced DNA damage by enhancing endogenous DNA repair capacity. Here we show that topical pTT pretreatment enhances the rate of DNA photoproduct removal, decreases UV-induced mutations, and reduces photocarcinogenesis in UV-irradiated hairless WT repair-proficient and Xpc(+/-) heterozygous partially repair-deficient mice, both transgenic for the lacZ/pUR288 mutation-indicator gene. These data support the existence of inducible mammalian DNA damage responses that increase DNA repair capacity after DNA damage and hence reduce the impact of future exposures to environmental carcinogens. The ability of topically applied pTT to induce protective physiologic responses that normally result from DNA damage suggests a previously undescribed means of reducing skin cancer in high-risk individuals.

SUBMITTER: Goukassian DA

PROVIDER: S-EPMC374347 | biostudies-literature | 2004 Mar

REPOSITORIES: biostudies-literature

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Topical DNA oligonucleotide therapy reduces UV-induced mutations and photocarcinogenesis in hairless mice.

Goukassian David A DA Helms Elizabeth E van Steeg Harry H van Oostrom Conny C Bhawan Jag J Gilchrest Barbara A BA

Proceedings of the National Academy of Sciences of the United States of America 20040303 11

UV-induced DNA damage gives rise to mutations and skin cancer. We have previously reported that treatment of skin cells in vitro with thymidine dinucleotide (pTT) activates p53 and increases the ability of cells to repair subsequent UV-induced DNA damage by enhancing endogenous DNA repair capacity. Here we show that topical pTT pretreatment enhances the rate of DNA photoproduct removal, decreases UV-induced mutations, and reduces photocarcinogenesis in UV-irradiated hairless WT repair-proficient ...[more]

PMID: 14999099

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Project description:Estrogen receptors (ER), including ER-α and ER-β, are known to regulate multiple biologic responses in various cell types. The expression of ER-β is lost in various cancers. ER-β agonists were shown to modulate inflammation, cancer cell proliferation, and differentiation. Here, we investigated the cancer chemopreventive properties of Erb-041, an ER-β agonist, using a model of UVB-induced photocarcinogenesis in SKH-1 mice. Erb-041 significantly reduced UVB-induced carcinogenesis. Tumor numbers and volume were reduced by 60% and 84%, respectively, in the Erb-041-treated group as compared with UVB (alone) control. This inhibition in tumorigenesis was accompanied by the decrease in proliferating cell nuclear antigen (PCNA), cyclin D1, VEGF, and CD31, and an increase in apoptosis. The lost ER-β expression in squamous cell carcinomas (SCC) was significantly recovered by Erb-041 treatment. In addition, the UVB-induced inflammatory responses were remarkably reduced. Myeloperoxidase activity, levels of cytokines (interleukin (IL)-1β, IL-6, and IL-10), and expression of p-ERK (extracellular signal-regulated kinase) 1/2, p-p38, p-IκB, iNOS, COX-2, and nuclear NF-κBp65 were diminished. The number of tumor-associated inflammatory cells (GR-1(+)/CD11b(+) and F4/80(+)) was also decreased. Tumors excised from Erb-041-treated animal were less invasive and showed reduced epithelial-mesenchymal transition (EMT). The enhanced expression of E-cadherin with the concomitantly reduced expression of N-cadherin, Snail, Slug, and Twist characterized these lesions. The WNT/β-catenin signaling pathway, which underlies pathogenesis of skin cancer, was found to be downregulated by Erb-041 treatment. Similar but not identical changes in proliferation and EMT regulatory proteins were noticed following treatment of tumor cells with a WNT signaling inhibitor XAV939. Our results show that Erb-041 is a potent skin cancer chemopreventive agent that acts by dampening the WNT/β-catenin signaling pathway.

Project description:An urgent need exists for the development of more efficacious molecular strategies targeting nonmelanoma skin cancer (NMSC), the most common malignancy worldwide. Inflammatory signaling downstream of Toll-like receptor 4 (TLR4) has been implicated in several forms of tumorigenesis, yet its role in solar UV-induced skin carcinogenesis remains undefined. We have previously shown in keratinocyte cell culture and SKH-1 mouse epidermis that topical application of the specific TLR4 antagonist resatorvid (TAK-242) blocks acute UV-induced AP-1 and NF-?B signaling, associated with downregulation of inflammatory mediators and MAP kinase phosphorylation. We therefore explored TLR4 as a novel target for chemoprevention of UV-induced NMSC. We selected the clinical TLR4 antagonist resatorvid based upon target specificity, potency, and physicochemical properties. Here, we confirm using ex vivo permeability assays that topical resatorvid can be effectively delivered to skin, and using in vivo studies that topical resatorvid can block UV-induced AP-1 activation in mouse epidermis. We also report that in a UV-induced skin tumorigenesis model, topical resatorvid displays potent photochemopreventive activity, significantly suppressing tumor area and multiplicity. Tumors harvested from resatorvid-treated mice display reduced activity of UV-associated signaling pathways and a corresponding increase in apoptosis compared with tumors from control animals. Further mechanistic insight on resatorvid-based photochemoprevention was obtained from unsupervised hierarchical clustering analysis of protein readouts via reverse-phase protein microarray revealing a significant attenuation of key UV-induced proteomic changes by resatorvid in chronically treated high-risk SKH-1 skin prior to tumorigenesis. Taken together, our data identify TLR4 as a novel molecular target for topical photochemoprevention of NMSC. Cancer Prev Res; 11(5); 265-78. ©2018 AACRSee related editorial by Sfanos, p. 251.

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Topical DNA oligonucleotide therapy reduces UV-induced mutations and photocarcinogenesis in hairless mice.

Publications

Topical DNA oligonucleotide therapy reduces UV-induced mutations and photocarcinogenesis in hairless mice.

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