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Title: The effects of NRF2 modulation on the initiation and progression of chemically and genetically induced lung cancer.

Authors: Tao, Shasha; Rojo de la Vega, Montserrat; Chapman, Eli; Ooi, Aikseng; Zhang, Donna D

Published In Mol Carcinog, (2018 02)

Abstract: Targeting the transcription factor NRF2 has been recognized as a feasible strategy for cancer prevention and treatment, but many of the mechanistic details underlying its role in cancer development and progression are lacking. Therefore, careful mechanistic studies of the NRF2 pathway in cancer initiation and progression are needed to identify which therapeutic avenue-activation or inhibition-is appropriate in a given context. Moreover, while numerous reports confirm the protective effect of NRF2 activation against chemical carcinogenesis little is known of its role in cancer arising from spontaneous mutations. Here, we tested the effects of NRF2 modulation (activation by sulforaphane or inhibition by brusatol) in lung carcinogenesis using a chemical (vinyl carbamate) model in A/J mice and a genetic (conditional KrasG12D oncogene expression, to simulate spontaneous oncogene mutation) model in C57BL/6J mice. Mice were treated with NRF2 modulators before carcinogen exposure or KrasG12D expression to test the role of NRF2 in cancer initiation, or treated after tumor development to test the role of NRF2 in cancer progression. Lung tissues were analyzed to determine tumor burden, as well as status of NRF2 and KRAS pathways. Additionally, proliferation, apoptosis, and oxidative DNA damage were assessed. Overall, NRF2 activation prevents initiation of chemically induced cancer, but promotes progression of pre-existing tumors regardless of chemical or genetic etiology. Once tumors are initiated, NRF2 inhibition is effective against the progression of chemically and spontaneously induced tumors. These results have important implications for NRF2-targeted cancer prevention and intervention strategies.

PubMed ID: 28976703 Exiting the NIEHS site

MeSH Terms: Animals; Anticarcinogenic Agents/pharmacology; Apoptosis/drug effects; Apoptosis/genetics; Carcinogenesis/drug effects; Carcinogenesis/genetics; Cell Proliferation/drug effects; Cell Proliferation/genetics; DNA Damage/drug effects; DNA Damage/genetics; Disease Progression; Isothiocyanates/pharmacology; Lung Neoplasms/drug therapy; Lung Neoplasms/genetics*; Lung Neoplasms/pathology; Male; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2/genetics*; Oxidative Stress/drug effects; Oxidative Stress/genetics; Proto-Oncogene Proteins p21(ras)/genetics; Quassins/pharmacology; Signal Transduction/drug effects; Signal Transduction/genetics; Tumor Burden/drug effects; Tumor Burden/genetics; Urethane/analogs & derivatives; Urethane/pharmacology

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