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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{sub 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-{kappa}B during UV-induced skin carcinogenesis. Taken together, our results identify norathyriolmore » as a safe new chemopreventive agent that is highly effective against development of UV-induced skin cancer.« less

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ;  [1]
  1. Cornell
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1039445
Resource Type:
Journal Article
Journal Name:
Cancer Res.
Additional Journal Information:
Journal Volume: 72; Journal Issue: 01, 2012; Journal ID: ISSN 0008-5472
Country of Publication:
United States
Language:
ENGLISH
Subject:
08 HYDROGEN; ADENINES; CARCINOGENESIS; HYDROGEN; IN VITRO; IRRADIATION; MEDICINE; METABOLITES; PHOSPHORYLATION; PHOSPHOTRANSFERASES; PROTEINS; ULTRAVIOLET RADIATION

Citation Formats

Li, Jixia, Malakhova, Margarita, Mottamal, Madhusoodanan, Reddy, Kanamata, Kurinov, Igor, Carper, Andria, Langfald, Alyssa, Oi, Naomi, Kim, Myoung Ok, Zhu, Feng, Sosa, Carlos P, Zhou, Keyuan, Bode, Ann M, Dong, Zigang, Guangdong), and UMM). Norathyriol Suppresses Skin Cancers Induced by Solar Ultraviolet Radiation by Targeting ERK Kinases. United States: N. p., 2012. Web. doi:10.1158/0008-5472.CAN-11-2596.
Li, Jixia, Malakhova, Margarita, Mottamal, Madhusoodanan, Reddy, Kanamata, Kurinov, Igor, Carper, Andria, Langfald, Alyssa, Oi, Naomi, Kim, Myoung Ok, Zhu, Feng, Sosa, Carlos P, Zhou, Keyuan, Bode, Ann M, Dong, Zigang, Guangdong), & UMM). Norathyriol Suppresses Skin Cancers Induced by Solar Ultraviolet Radiation by Targeting ERK Kinases. United States. https://doi.org/10.1158/0008-5472.CAN-11-2596
Li, Jixia, Malakhova, Margarita, Mottamal, Madhusoodanan, Reddy, Kanamata, Kurinov, Igor, Carper, Andria, Langfald, Alyssa, Oi, Naomi, Kim, Myoung Ok, Zhu, Feng, Sosa, Carlos P, Zhou, Keyuan, Bode, Ann M, Dong, Zigang, Guangdong), and UMM). 2012. "Norathyriol Suppresses Skin Cancers Induced by Solar Ultraviolet Radiation by Targeting ERK Kinases". United States. https://doi.org/10.1158/0008-5472.CAN-11-2596.
@article{osti_1039445,
title = {Norathyriol Suppresses Skin Cancers Induced by Solar Ultraviolet Radiation by Targeting ERK Kinases},
author = {Li, Jixia and Malakhova, Margarita and Mottamal, Madhusoodanan and Reddy, Kanamata and Kurinov, Igor and Carper, Andria and Langfald, Alyssa and Oi, Naomi and Kim, Myoung Ok and Zhu, Feng and Sosa, Carlos P and Zhou, Keyuan and Bode, Ann M and Dong, Zigang and Guangdong) and UMM)},
abstractNote = {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{sub 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-{kappa}B 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.},
doi = {10.1158/0008-5472.CAN-11-2596},
url = {https://www.osti.gov/biblio/1039445}, journal = {Cancer Res.},
issn = {0008-5472},
number = 01, 2012,
volume = 72,
place = {United States},
year = {Wed Jun 27 00:00:00 EDT 2012},
month = {Wed Jun 27 00:00:00 EDT 2012}
}