title: Norathyriol suppresses skin cancers induced by solar ultraviolet radiation by targeting ERK kinases.
abstract: Ultraviolet (UV) irradiation is the leading factor in the development of skin cancer, prompting great interest in chemopreventive agents for this disease. In this study, we report the discovery of norathyriol, a plant-derived chemopreventive compound identified through an in silico virtual screening of the Chinese Medicine Library. Norathyriol is a metabolite of mangiferin found in mango, Hypericum elegans, and Tripterospermum lanceolatum and is known to have anticancer activity. Mechanistic investigations determined that norathyriol acted as an inhibitor of extracellular signal-regulated kinase (ERK)1/2 activity to attenuate UVB-induced phosphorylation in mitogen-activated protein kinases signaling cascades. We confirmed the direct and specific binding of norathyriol with ERK2 through a cocrystal structural analysis. The xanthone moiety in norathyriol acted as an adenine mimetic to anchor the compound by hydrogen bonds to the hinge region of the protein ATP-binding site on ERK2. Norathyriol inhibited in vitro cell growth in mouse skin epidermal JB6 P+ cells at the level of G(2)-M phase arrest. In mouse skin tumorigenesis assays, norathyriol significantly suppressed solar UV-induced skin carcinogenesis. Further analysis indicated that norathyriol mediates its chemopreventive activity by inhibiting the ERK-dependent activity of transcriptional factors AP-1 and NF-κB during UV-induced skin carcinogenesis. Taken together, our results identify norathyriol as a safe new chemopreventive agent that is highly effective against development of UV-induced skin cancer.
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA.
authors.forename: Jixia
authors.initials: J
authors.lastname: Li
authors.forename: Margarita
authors.initials: M
authors.lastname: Malakhova
authors.forename: Madhusoodanan
authors.initials: M
authors.lastname: Mottamal
authors.forename: Kanamata
authors.initials: K
authors.lastname: Reddy
authors.forename: Igor
authors.initials: I
authors.lastname: Kurinov
authors.forename: Andria
authors.initials: A
authors.lastname: Carper
authors.forename: Alyssa
authors.initials: A
authors.lastname: Langfald
authors.forename: Naomi
authors.initials: N
authors.lastname: Oi
authors.forename: Myoung Ok
authors.initials: MO
authors.lastname: Kim
authors.forename: Feng
authors.initials: F
authors.lastname: Zhu
authors.forename: Carlos P
authors.initials: CP
authors.lastname: Sosa
authors.forename: Keyuan
authors.initials: K
authors.lastname: Zhou
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000818:Animals; D015153:Blotting, Western; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D005260:Female; D051379:Mice; D008958:Models, Molecular; D009381:Neoplasms, Radiation-Induced / Q000209:etiology / Q000517:prevention & control*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000209:etiology / Q000517:prevention & control*; D013472:Sunlight; D014966:Xanthenes / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D014966:Xanthenes; C069053:norathyriol; D048049:Extracellular Signal-Regulated MAP Kinases
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