Pharmacological TLR4 antagonism using topical resatorvid blocks solar UV-induced skin tumorigenesis in SKH-1 mice

Karen Blohm-Mangone, Nichole B. Burkett, Shekha Tahsin, Paul B. Myrdal, Alhassan Aodah, Brenda Ho, Jaroslav Janda, Michelle McComas, Kathylynn Saboda, Denise J. Roe, Zigang Dong, Ann M. Bode, Emanuel F. Petricoin, Valerie S. Calvert, Clara Curiel-Lewandrowski, David S. Alberts, Georg T. Wondrak, Sally E. Dickinson

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

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 UVinduced AP-1 and NF-kB 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.

Original languageEnglish (US)
Pages (from-to)265-277
Number of pages13
JournalCancer Prevention Research
Volume11
Issue number5
DOIs
StatePublished - May 2018

Bibliographical note

Funding Information:
All data were generated with the support of the following NIH grants: NCI P01 CA027502, Cancer Center Support Grant P30 CA023074 using the Tissue Acquisition and Cellular/Molecular Analysis Shared Resource, R03 CA212719, and pilot funding from the University of Arizona Skin Cancer Institute (SCI). The authors wish to acknowledge the contributions of Mary Krutzsch, Michael Yoswiak, and Dr. Agnes Witkiewicz.

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