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Cancer Prevention Research
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Research Article

(+)-2-(1-Hydroxyl-4-Oxocyclohexyl) Ethyl Caffeate Suppresses Solar UV-Induced Skin Carcinogenesis by Targeting PI3K, ERK1/2, and p38

Do Young Lim, Mee-Hyun Lee, Seung Ho Shin, Hanyoung Chen, Joohyun Ryu, Lei Shan, Honglin Li, Ann M. Bode, Wei-Dong Zhang and Zigang Dong
Do Young Lim
1The Hormel Institute, University of Minnesota, Austin, Minnesota;
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Mee-Hyun Lee
1The Hormel Institute, University of Minnesota, Austin, Minnesota;
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Seung Ho Shin
1The Hormel Institute, University of Minnesota, Austin, Minnesota;
4Program in Biomedical Informatics and Computational Biology, University of Minnesota, Minneapolis, Minnesota.
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Hanyoung Chen
1The Hormel Institute, University of Minnesota, Austin, Minnesota;
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Joohyun Ryu
1The Hormel Institute, University of Minnesota, Austin, Minnesota;
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Lei Shan
2Department of Natural Product Chemistry, Second Military Medical University;
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Honglin Li
3School of Pharmacy, East China University of Science & Technology, Shanghai, PR China; and
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Ann M. Bode
1The Hormel Institute, University of Minnesota, Austin, Minnesota;
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Wei-Dong Zhang
2Department of Natural Product Chemistry, Second Military Medical University;
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  • For correspondence: zgdong@hi.umn.edu wdzhangy@hotmail.com
Zigang Dong
1The Hormel Institute, University of Minnesota, Austin, Minnesota;
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  • For correspondence: zgdong@hi.umn.edu wdzhangy@hotmail.com
DOI: 10.1158/1940-6207.CAPR-13-0286 Published August 2014
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Abstract

For decades, skin cancer incidence has increased, mainly because of oncogenic signaling pathways activated by solar ultraviolet (UV) irradiation (i.e., sun exposure). Solar UV induces multiple signaling pathways that are critical in the development of skin cancer, and therefore the development of compounds capable of targeting multiple molecules for chemoprevention of skin carcinogenesis is urgently needed. Herein, we examined the chemopreventive effects and the molecular mechanism of (+)-2-(1-hydroxyl-4-oxocyclohexyl) ethyl caffeate (HOEC), isolated from Incarvillea mairei var. grandiflora (Wehrhahn) Grierson. HOEC strongly inhibited neoplastic transformation of JB6 Cl41 cells without toxicity. PI3K, ERK1/2, and p38 kinase activities were suppressed by direct binding with HOEC in vitro. Our in silico docking data showed that HOEC binds at the ATP-binding site of each kinase. The inhibition of solar UV-induced PI3K, ERK1/2, and p38 kinase activities resulted in suppression of their downstream signaling pathways and AP1 and NF-κB transactivation in JB6 cells. Furthermore, topical application of HOEC reduced skin cancer incidence and tumor volume in SKH-1 hairless mice chronically exposed to solar UV. In summary, our results show that HOEC exerts inhibitory effects on multiple kinase targets and their downstream pathways activated by solar UV in vitro and in vivo. These findings suggest that HOEC is a potent chemopreventive compound against skin carcinogenesis caused by solar UV exposure. Cancer Prev Res; 7(8); 856–65. ©2014 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Prevention Research Online (http://cancerprevres.aacrjournals.org/).

  • Received August 1, 2013.
  • Revision received May 14, 2014.
  • Accepted May 16, 2014.
  • ©2014 American Association for Cancer Research.
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Cancer Prevention Research: 7 (8)
August 2014
Volume 7, Issue 8
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(+)-2-(1-Hydroxyl-4-Oxocyclohexyl) Ethyl Caffeate Suppresses Solar UV-Induced Skin Carcinogenesis by Targeting PI3K, ERK1/2, and p38
Do Young Lim, Mee-Hyun Lee, Seung Ho Shin, Hanyoung Chen, Joohyun Ryu, Lei Shan, Honglin Li, Ann M. Bode, Wei-Dong Zhang and Zigang Dong
Cancer Prev Res August 1 2014 (7) (8) 856-865; DOI: 10.1158/1940-6207.CAPR-13-0286

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(+)-2-(1-Hydroxyl-4-Oxocyclohexyl) Ethyl Caffeate Suppresses Solar UV-Induced Skin Carcinogenesis by Targeting PI3K, ERK1/2, and p38
Do Young Lim, Mee-Hyun Lee, Seung Ho Shin, Hanyoung Chen, Joohyun Ryu, Lei Shan, Honglin Li, Ann M. Bode, Wei-Dong Zhang and Zigang Dong
Cancer Prev Res August 1 2014 (7) (8) 856-865; DOI: 10.1158/1940-6207.CAPR-13-0286
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