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

Shasha Tao, Montserrat Rojo de la Vega, Eli Chapman, Aikseng Ooi, Donna Zhang

Research output: Contribution to journalArticle

22 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)182-192
Number of pages11
JournalMolecular Carcinogenesis
Volume57
Issue number2
DOIs
StatePublished - Feb 1 2018

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Keywords

  • brusatol
  • carcinogenesis
  • chemoprevention
  • sulforaphane
  • vinyl carbamate

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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