Zerumbone Induces Heme Oxygenase-1 Expression in Mouse Skin and Cultured Murine Epidermal Cells through Activation of Nrf2

Abstract

Zerumbone, a sesquiterpene derived from tropical ginger, contains an electrophilic a,b-unsaturated carbonyl moiety and was found to suppress chemically induced papilloma formation in mouse skin. Here, we report that topical application of zerumbone onto dorsal skin of hairless mice induces activation of NF-E2-related factor 2 (Nrf2) and expression of heme oxygenase-1 (HO-1). We compared the levels of HO-1 protein in the skin of zerumbone-treated Nrf2 wild-type and Nrf2 knockout mice, and nrf2-deficient mice expressed HO-1 protein to a much lesser extent than the wild-type animals following topical application of zerumbone. Treatment of mouse epidermal JB6 cells with zerumbone caused a marked increase of Nrf2 nuclear translocation followed by the promoter activity of HO-1, and also enhanced direct binding of Nrf2 to the antioxidant response element. Moreover, knockdown of Nrf2 in JB6 cells diminished the zerumbone-induced upregulation of HO-1. Notably, a-humulene and 8-hydroxy-a-humulene, the structural analogues of zerumbone that lack the a,b-unsaturated carbonyl group, failed to activate Nrf2 and were unable to increase HO-1 expression. Unlike zerumbone, these nonelectrophilic analogues could not suppress the 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced JB6 cell transformation and the intracellular accumulation of reactive oxygen species (ROS). Interestingly, when JB6 cells were treated with carbon monoxide-releasing molecule that mimics the HO-1 activity, the TPA-induced ROS production was markedly reduced. Taken together, these findings suggest that upregulation of HO-1 expression by zerumbone is mediated through activation of Nrf2 signaling, which provides a mechanistic basis for the chemopreventive effects of this sesquiterpene on mouse skin carcinogenesis. Cancer Prev Res; 4(6); 860-70. Ó2011 AACR.

Role of Activating Transcription Factor 3 (ATF3) in Endoplasmic Reticulum (ER) Stress-induced Sensitization of p53-deficient Human Colon Cancer Cells to Tumor Necrosis Factor (TNF)-related Apoptosis-inducing Ligand (TRAIL)-mediated Apoptosis through Up-regulation of Death Receptor 5 (DR5) by Zerumbone and Celecoxib

“…This study also showed that ZER-induced DR5 expression was abolished by ROS scavengers, consistent with a previous report (30,53,54). More recently, it has been reported that ZER induces cellular proteostress through its binding to cellular proteins to activate the ubiquitin-proteasome system or heat shock response (36,37).…”

UVA-induced protection of skin through the induction of heme oxygenase-1

“…For example, Hirota found that Nrf2 might play an important role in the protection of the skin against UVA irradiation in mice fibroblasts (31). Later, Nrf2-driven HO-1 expression was found to protect mouse skin cells from oxidative carcinogenesis (32). Our studies also showed that Nrf2 might protect human skin fibroblasts and keratinocytes from UVA irradiation (23,33).…”

Blocking of JB6 Cell Transformation by Tanshinone IIA: Epigenetic Reactivation of Nrf2 Antioxidative Stress Pathway

“…*P<0.05 and #P<0.01, respectively, indicate significant differences between the treatment and control group of antioxidant response genes. Numerous studies have provided strong evidence for a relationship between Nrf2 deficiency and increased susceptibility to carcinogenesis, and elimination of carcinogens through induction of cytoprotective enzymes is one important approach to prevent cancer (20). In our previous study, we have shown that the , and DNMT3b as well as HDAC1, HDAC3, HDAC4, and HDAC8 mRNA and proteins was detected by real-time PCR and Western blotting, respectively.…”

“…JB6 P+ is a normal skin keratinocyte cell line that will transform under carcinogenic or environmental challenges including TPA, EGF, and UVB (20). Therefore, this model has been widely used for skin cancer risk assessment.…”