1,8-cineole prevents UVB-induced skin carcinogenesis by targeting the aryl hydrocarbon receptor

// Jangho Lee 1, 2, * , Su Jeong Ha 2, 3, * , Joon Park 2, 4 , Yong Ho Kim 2 , Nam Hyouck Lee 2 , Young Eon Kim 2 , Yoonsook Kim 2 , Kyung-Mo Song 2 and Sung Keun Jung 1, 2 1 Department of Food Biotechnology, Korea University of Science and Technology, Daejeon 34113, Republic of Korea 2 Division of Functional Food Research, Korea Food Research Institute, Gyeonggi-do 13539, Republic of Korea 3 Department of Agricultural Biotechnology, Seoul National University, Seoul 151-921, Republic of Korea 4 Department of Food Bioscience and Technology, Korea University, Seoul 02841, Republic of Korea * These authors have contributed equally to this work Correspondence to: Sung Keun Jung, email: skjung@kfri.re.kr 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 ABSTRACT 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 E 2 (PGE 2 ) 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.