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 Roe, Zigang Dong, Ann M. Bode, Emanuel F. Petricoin, Valerie S. Calvert, Clara N Curiel, David S Alberts, Georg T Wondrak, Sally E Dickinson

Research output: Contribution to journalArticle

5 Citations (Scopus)

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 1 2018

Fingerprint

Toll-Like Receptor 4
Carcinogenesis
Pharmacology
Skin
Skin Neoplasms
Transcription Factor AP-1
Epidermis
Neoplasms
ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate
Protein Array Analysis
NF-kappa B
Chemoprevention
Keratinocytes
Proteomics
Cluster Analysis
Permeability
Phosphotransferases
Down-Regulation
Cell Culture Techniques
Phosphorylation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Pharmacological TLR4 antagonism using topical resatorvid blocks solar UV-induced skin tumorigenesis in SKH-1 mice. / Blohm-Mangone, Karen; Burkett, Nichole B.; Tahsin, Shekha; Myrdal, Paul B; Aodah, Alhassan; Ho, Brenda; Janda, Jaroslav; McComas, Michelle; Saboda, Kathylynn; Roe, Denise; Dong, Zigang; Bode, Ann M.; Petricoin, Emanuel F.; Calvert, Valerie S.; Curiel, Clara N; Alberts, David S; Wondrak, Georg T; Dickinson, Sally E.

In: Cancer Prevention Research, Vol. 11, No. 5, 01.05.2018, p. 265-277.

Research output: Contribution to journalArticle

Blohm-Mangone, K, Burkett, NB, Tahsin, S, Myrdal, PB, Aodah, A, Ho, B, Janda, J, McComas, M, Saboda, K, Roe, D, Dong, Z, Bode, AM, Petricoin, EF, Calvert, VS, Curiel, CN, Alberts, DS, Wondrak, GT & Dickinson, SE 2018, 'Pharmacological TLR4 antagonism using topical resatorvid blocks solar UV-induced skin tumorigenesis in SKH-1 mice', Cancer Prevention Research, vol. 11, no. 5, pp. 265-277. https://doi.org/10.1158/1940-6207.CAPR-17-0349
Blohm-Mangone, Karen ; Burkett, Nichole B. ; Tahsin, Shekha ; Myrdal, Paul B ; Aodah, Alhassan ; Ho, Brenda ; Janda, Jaroslav ; McComas, Michelle ; Saboda, Kathylynn ; Roe, Denise ; Dong, Zigang ; Bode, Ann M. ; Petricoin, Emanuel F. ; Calvert, Valerie S. ; Curiel, Clara N ; Alberts, David S ; Wondrak, Georg T ; Dickinson, Sally E. / Pharmacological TLR4 antagonism using topical resatorvid blocks solar UV-induced skin tumorigenesis in SKH-1 mice. In: Cancer Prevention Research. 2018 ; Vol. 11, No. 5. pp. 265-277.
@article{bd527c5a8f9644cfa656bd42901d1dfb,
title = "Pharmacological TLR4 antagonism using topical resatorvid blocks solar UV-induced skin tumorigenesis in SKH-1 mice",
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.",
author = "Karen Blohm-Mangone and Burkett, {Nichole B.} and Shekha Tahsin and Myrdal, {Paul B} and Alhassan Aodah and Brenda Ho and Jaroslav Janda and Michelle McComas and Kathylynn Saboda and Denise Roe and Zigang Dong and Bode, {Ann M.} and Petricoin, {Emanuel F.} and Calvert, {Valerie S.} and Curiel, {Clara N} and Alberts, {David S} and Wondrak, {Georg T} and Dickinson, {Sally E}",
year = "2018",
month = "5",
day = "1",
doi = "10.1158/1940-6207.CAPR-17-0349",
language = "English (US)",
volume = "11",
pages = "265--277",
journal = "Cancer Prevention Research",
issn = "1940-6207",
publisher = "American Association for Cancer Research Inc.",
number = "5",

}

TY - JOUR

T1 - Pharmacological TLR4 antagonism using topical resatorvid blocks solar UV-induced skin tumorigenesis in SKH-1 mice

AU - Blohm-Mangone, Karen

AU - Burkett, Nichole B.

AU - Tahsin, Shekha

AU - Myrdal, Paul B

AU - Aodah, Alhassan

AU - Ho, Brenda

AU - Janda, Jaroslav

AU - McComas, Michelle

AU - Saboda, Kathylynn

AU - Roe, Denise

AU - Dong, Zigang

AU - Bode, Ann M.

AU - Petricoin, Emanuel F.

AU - Calvert, Valerie S.

AU - Curiel, Clara N

AU - Alberts, David S

AU - Wondrak, Georg T

AU - Dickinson, Sally E

PY - 2018/5/1

Y1 - 2018/5/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85047782140&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85047782140&partnerID=8YFLogxK

U2 - 10.1158/1940-6207.CAPR-17-0349

DO - 10.1158/1940-6207.CAPR-17-0349

M3 - Article

C2 - 29437671

AN - SCOPUS:85047782140

VL - 11

SP - 265

EP - 277

JO - Cancer Prevention Research

JF - Cancer Prevention Research

SN - 1940-6207

IS - 5

ER -