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

Jangho Lee,Sung Keun Jung,Yong Ho Kim,Yoonsook Kim,Su Jeong Ha,Young Eon Kim,Joon Park,Nam Hyouck Lee,Kyung-Mo Song

doi:10.18632/oncotarget.22519

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 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.

Highlights

Skin cancer is the most common cancer type diagnosed in Caucasians, and its incidence is increasing annually [1, 2]
We investigated the effect of 1,8-cineole on UVB-induced skin carcinogenesis. 1,8-cineole inhibited UVBinduced cyclooxygenase-2 (COX-2) protein and mRNA expression and prostaglandin E2 (PGE2) generation in HaCaT cells. 1,8-cineole inhibited phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, and phosphorylation of its upstream kinases, c-Src and epidermal growth factor receptor (EGFR)
The World Health Organization (WHO) indicates that approximately 35% of all deaths caused by cancer are preventable, and some phytochemicals have been reported to prevent carcinogenesis by inhibiting the cellular signaling pathways involved in tumor promotion [14]

Summary

INTRODUCTION

Skin cancer is the most common cancer type diagnosed in Caucasians, and its incidence is increasing annually [1, 2]. Expression and increased COX-2 levels are associated with the development of various cancer types including skin cancer [4, 5]. Exposure to UVB activates various signaling intermediates including MAPK, PI3K/Akt and AhR, via which COX-2 expression is regulated [6]. Multiple lines of evidence have shown that targeting these signaling pathways can be an effective strategy to suppress UVB-induced COX-2 expression and skin cancer [7]. A previous study has reported that AhR knockout (AhR-/-) mice exhibit resistance to benzo[a] pyrene-induced skin carcinogenesis [11]. UVB irradiation activates AhR and subsequently induces COX-2 expression [12]. 1,8-cineole has promising potential to prevent skin carcinogenesis by regulating COX-2 expression, the extent of its preventive effect and the underlying mechanism responsible has remained unknown

RESULTS

DISCUSSION

Findings

MATERIALS AND METHODS