1,8-cineole prevents UVB-induced skin carcinogenesis by targeting the aryl hydrocarbon receptor
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Jangho Lee1,2,*, Su Jeong Ha2,3,*, Joon Park2,4, Yong Ho Kim2, Nam Hyouck Lee2, Young Eon Kim2, Yoonsook Kim2, Kyung-Mo Song2 and Sung Keun Jung1,2
1Department of Food Biotechnology, Korea University of Science and Technology, Daejeon 34113, Republic of Korea
2Division of Functional Food Research, Korea Food Research Institute, Gyeonggi-do 13539, Republic of Korea
3Department of Agricultural Biotechnology, Seoul National University, Seoul 151-921, Republic of Korea
4Department of Food Bioscience and Technology, Korea University, Seoul 02841, Republic of Korea
*These authors have contributed equally to this work
Sung Keun Jung, email: [email protected]
Keywords: 1,8-cineole; aryl hydrocarbon receptor; skin cancer; cyclooxygenase-2; drug affinity responsive target stability
Received: June 20, 2017 Accepted: October 30, 2017 Published: November 20, 2017
1,8-cineole is a natural monoterpene cyclic ether present in Eucalyptus, and has been reported to exhibit anti-inflammatory and antioxidant effects. However, the preventive effect of 1,8-cineole on skin carcinogenesis and the molecular mechanism of action responsible remains unknown. In the present study, we investigated the effect of 1,8-cineole on UVB-induced skin carcinogenesis. 1,8-cineole inhibited UVB-induced cyclooxygenase-2 (COX-2) protein and mRNA expression and prostaglandin E2 (PGE2) generation in HaCaT cells. 1,8-cineole also inhibited phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, and phosphorylation of its upstream kinases, c-Src and epidermal growth factor receptor (EGFR). Quantitative real-time RT-PCR (qRT-PCR) and drug affinity responsive target stability (DARTS) assay results showed that 1,8-cineole suppressed UVB-induced expression of a target gene of the aryl hydrocarbon receptor (AhR), cyp1a1, and directly binds to AhR. Knockdown of AhR suppressed COX-2 expression as well as phosphorylation of ERK1/2 in HaCaT cells. Furthermore, topical treatment of 1,8-cineole on mouse skin delayed tumor incidence and reduced tumor numbers, while inhibiting COX-2 expression in vivo. Taken together, these results suggest that 1,8-cineole is a potent chemopreventive agent that inhibits UVB-induced COX-2 expression by targeting AhR to suppress UVB-induced skin carcinogenesis.
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