Novel function of transcription factor Nrf2 as an inhibitor of RON tyrosine kinase receptor-mediated cancer cell invasion

Amalraj Thangasamy, Jessica Rogge, Naveen K. Krishnegowda, James W. Freeman, Sudhakar Ammanamanchi

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Recepteur d' origine nantais (RON), a tyrosine kinase receptor, is aberrantly expressed in human tumors and promotes cancer cell invasion.RONreceptor activation is also associated with resistance to tamoxifen treatment in breast cancer cells. Nrf2 is a positive regulator of cytoprotective genes. Using chromatin immunoprecipitation (ChIP) and site-directed mutagenesis studies of the RON promoter, we identified Nrf2 as a negative regulator of RON gene expression. High Nrf2 and low RON expression was observed in normal mammary tissue whereas high RON and low or undetectable expression of Nrf2 was observed in breast tumors. The Nrf2 inducer sulforaphane (SFN) as well as ectopic Nrf2 expression or knock-down of the Nrf2 negative regulator keap1, which stabilizes Nrf2, inhibited RONexpression and invasion of carcinoma cells. Consequently, our studies identified a novel functional role for Nrf2 as a "repressor" andRONkinase as a molecular target of SFN, which mediates the anti-tumor effects of SFN. These results are not limited to breast cancer cells since the Nrf2 inducer SFN stabilized Nrf2 and inhibited RON expression in carcinoma cells from various tumor types.

Original languageEnglish (US)
Pages (from-to)32115-32122
Number of pages8
JournalJournal of Biological Chemistry
Volume286
Issue number37
DOIs
StatePublished - Sep 16 2011

Fingerprint

Receptor Protein-Tyrosine Kinases
Transcription Factors
Cells
Tumors
Neoplasms
Breast Neoplasms
Carcinoma
Mutagenesis
Chromatin Immunoprecipitation
Tamoxifen
Regulator Genes
Site-Directed Mutagenesis
Gene expression
Chromatin
RON protein
Breast
Genes
Chemical activation
Tissue
Gene Expression

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Novel function of transcription factor Nrf2 as an inhibitor of RON tyrosine kinase receptor-mediated cancer cell invasion. / Thangasamy, Amalraj; Rogge, Jessica; Krishnegowda, Naveen K.; Freeman, James W.; Ammanamanchi, Sudhakar.

In: Journal of Biological Chemistry, Vol. 286, No. 37, 16.09.2011, p. 32115-32122.

Research output: Contribution to journalArticle

Thangasamy, Amalraj ; Rogge, Jessica ; Krishnegowda, Naveen K. ; Freeman, James W. ; Ammanamanchi, Sudhakar. / Novel function of transcription factor Nrf2 as an inhibitor of RON tyrosine kinase receptor-mediated cancer cell invasion. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 37. pp. 32115-32122.
@article{f02535f0b9104d2ea439f41e25c33151,
title = "Novel function of transcription factor Nrf2 as an inhibitor of RON tyrosine kinase receptor-mediated cancer cell invasion",
abstract = "Recepteur d' origine nantais (RON), a tyrosine kinase receptor, is aberrantly expressed in human tumors and promotes cancer cell invasion.RONreceptor activation is also associated with resistance to tamoxifen treatment in breast cancer cells. Nrf2 is a positive regulator of cytoprotective genes. Using chromatin immunoprecipitation (ChIP) and site-directed mutagenesis studies of the RON promoter, we identified Nrf2 as a negative regulator of RON gene expression. High Nrf2 and low RON expression was observed in normal mammary tissue whereas high RON and low or undetectable expression of Nrf2 was observed in breast tumors. The Nrf2 inducer sulforaphane (SFN) as well as ectopic Nrf2 expression or knock-down of the Nrf2 negative regulator keap1, which stabilizes Nrf2, inhibited RONexpression and invasion of carcinoma cells. Consequently, our studies identified a novel functional role for Nrf2 as a {"}repressor{"} andRONkinase as a molecular target of SFN, which mediates the anti-tumor effects of SFN. These results are not limited to breast cancer cells since the Nrf2 inducer SFN stabilized Nrf2 and inhibited RON expression in carcinoma cells from various tumor types.",
author = "Amalraj Thangasamy and Jessica Rogge and Krishnegowda, {Naveen K.} and Freeman, {James W.} and Sudhakar Ammanamanchi",
year = "2011",
month = "9",
day = "16",
doi = "10.1074/jbc.M111.245746",
language = "English (US)",
volume = "286",
pages = "32115--32122",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "37",

}

TY - JOUR

T1 - Novel function of transcription factor Nrf2 as an inhibitor of RON tyrosine kinase receptor-mediated cancer cell invasion

AU - Thangasamy, Amalraj

AU - Rogge, Jessica

AU - Krishnegowda, Naveen K.

AU - Freeman, James W.

AU - Ammanamanchi, Sudhakar

PY - 2011/9/16

Y1 - 2011/9/16

N2 - Recepteur d' origine nantais (RON), a tyrosine kinase receptor, is aberrantly expressed in human tumors and promotes cancer cell invasion.RONreceptor activation is also associated with resistance to tamoxifen treatment in breast cancer cells. Nrf2 is a positive regulator of cytoprotective genes. Using chromatin immunoprecipitation (ChIP) and site-directed mutagenesis studies of the RON promoter, we identified Nrf2 as a negative regulator of RON gene expression. High Nrf2 and low RON expression was observed in normal mammary tissue whereas high RON and low or undetectable expression of Nrf2 was observed in breast tumors. The Nrf2 inducer sulforaphane (SFN) as well as ectopic Nrf2 expression or knock-down of the Nrf2 negative regulator keap1, which stabilizes Nrf2, inhibited RONexpression and invasion of carcinoma cells. Consequently, our studies identified a novel functional role for Nrf2 as a "repressor" andRONkinase as a molecular target of SFN, which mediates the anti-tumor effects of SFN. These results are not limited to breast cancer cells since the Nrf2 inducer SFN stabilized Nrf2 and inhibited RON expression in carcinoma cells from various tumor types.

AB - Recepteur d' origine nantais (RON), a tyrosine kinase receptor, is aberrantly expressed in human tumors and promotes cancer cell invasion.RONreceptor activation is also associated with resistance to tamoxifen treatment in breast cancer cells. Nrf2 is a positive regulator of cytoprotective genes. Using chromatin immunoprecipitation (ChIP) and site-directed mutagenesis studies of the RON promoter, we identified Nrf2 as a negative regulator of RON gene expression. High Nrf2 and low RON expression was observed in normal mammary tissue whereas high RON and low or undetectable expression of Nrf2 was observed in breast tumors. The Nrf2 inducer sulforaphane (SFN) as well as ectopic Nrf2 expression or knock-down of the Nrf2 negative regulator keap1, which stabilizes Nrf2, inhibited RONexpression and invasion of carcinoma cells. Consequently, our studies identified a novel functional role for Nrf2 as a "repressor" andRONkinase as a molecular target of SFN, which mediates the anti-tumor effects of SFN. These results are not limited to breast cancer cells since the Nrf2 inducer SFN stabilized Nrf2 and inhibited RON expression in carcinoma cells from various tumor types.

UR - http://www.scopus.com/inward/record.url?scp=80052713227&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80052713227&partnerID=8YFLogxK

U2 - 10.1074/jbc.M111.245746

DO - 10.1074/jbc.M111.245746

M3 - Article

C2 - 21799005

AN - SCOPUS:80052713227

VL - 286

SP - 32115

EP - 32122

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 37

ER -