Novel Function of Transcription Factor Nrf2 as an Inhibitor of RON Tyrosine Kinase Receptor-mediated Cancer Cell Invasion

Recepteur d' origine nantais (RON), a tyrosine kinase receptor, is aberrantly expressed in human tumors and promotes cancer cell invasion. RON receptor activation is also associated with resistance to tamoxifen treatment in breast cancer cells. Nrf2 is a positive regulator of cytoprotective gen...

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Published in:The Journal of biological chemistry 2011-09, Vol.286 (37), p.32115-32122
Main Authors: Thangasamy, Amalraj, Rogge, Jessica, Krishnegowda, Naveen K., Freeman, James W., Ammanamanchi, Sudhakar
Format: Article
Language:English
Subjects:
Anticarcinogenic Agents - pharmacology
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Cell Line, Tumor
Female
Gene Expression
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
Gene Regulation
Humans
Isothiocyanates
Neoplasm Invasiveness
Neoplasm Proteins - metabolism
NF-E2-Related Factor 2 - metabolism
Promoter Regions, Genetic
Protein Stability - drug effects
Receptor Protein-Tyrosine Kinases - metabolism
Receptor Regulation
Receptor Tyrosine Kinase
Repressor Proteins - metabolism
Thiocyanates - pharmacology
Transcription Factors
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Summary:Recepteur d' origine nantais (RON), a tyrosine kinase receptor, is aberrantly expressed in human tumors and promotes cancer cell invasion. RON receptor 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 RON expression and invasion of carcinoma cells. Consequently, our studies identified a novel functional role for Nrf2 as a “repressor” and RON kinase 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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M111.245746