Norathyriol Suppresses Skin Cancers Induced by Solar Ultraviolet Radiation by Targeting ERK Kinases

Abstract

Ultraviolet (UV) irradiation is the most important factor contributing to the development of skin cancer. The use of chemopreventive agents, especially naturally occurring plant products, to prevent skin cancer caused by UV might an effective therapeutic or preventive intervention. Using in silico virtual screening of the Chinese Medicine Library, we identified norathyriol as a potential ERK2 inhibitor. Norathyriol is a metabolite of mangiferin, which is found in mango, Hypericum elegans, and Tripterospermum lanceolatum, and has potent anticancer-promoting activity. Here, we show that norathyriol inhibits ERK1/2 kinase activities and attenuates UVB-induced phosphorylation of the mitogen-activated protein kinase (MAPK) cascades. Direct binding of norathyriol with ERK2 was confirmed by a co-crystal structure. The norathyriol xanthone moiety acts as an adenine mimeric and anchors the compound by hydrogen bonds to the hinge region of the protein ATP-binding site. Norathyriol inhibited cell growth in mouse skin epidermal JB6 P+ cells by inducing G2-M phase arrest. Mouse skin tumorigenesis data clearly showed that treatment with norathyriol significantly suppressed solar UV-induced skin carcinogenesis in vivo. Results also indicated that norathyriol exhibits a potent chemopreventive activity through the inhibition of transcription factor AP-1 and NF-κB by targeting ERKs in UV-induced skin carcinogenesis.

Caffeic Acid Directly Targets ERK1/2 to Attenuate Solar UV-Induced Skin Carcinogenesis

“…Purification of the full length (residues 1–360) human ERK2 was performed as described previously (20). Briefly, a His-tagged ERK2 protein was purified on HisPur Ni-NTA resin (Thermo Scientific, Waltham, MA); the His-tag removed by incubation with thrombin; and the protein was re-purified by FPLC on a Superdex ™ 200 column.…”

“…X-ray diffraction data were integrated and scaled using the HKL2000 package (21). The structure was resolved by molecular replacement using a starting model of the refined ERK2/norathyriol structure (PDB code 3SA0) (20). All calculations were performed using PHENIX (22).…”

Kaempferol Targets RSK2 and MSK1 to Suppress UV Radiation-Induced Skin Cancer

“…Among the MAP kinase family, the ERKs cascade has been a focus of cancer chemoprevention because of its importance in carcinogenesis (6, 7). Abnormalities in the ERKs pathway play a critical role in the development and progression of cancer and its deregulation has been reported in approximately 1/3 of all human cancers (8). The p38 related signal transduction pathway is also markedly affected by SUV exposure (9).…”

The RAF-MEK-ERK Pathway: Targeting ERK to Overcome Obstacles of Effective Cancer Therapy

“…Through Chinese compound library in silica screening, Li et al reported the identification of norathyriol, a metabolite of mangiferin in mango [131]. In a ATP-competitive manner, norathyriol could significantly inhibit JB6 P + cells derived from UVB-induced MAPKs phosphorylation at the dose of norathyriol (10 μM), and had no obvious effect on JNKs or p38 [132].…”