Recepteur d'origine nantais tyrosine kinase is a direct target of hypoxia-inducible factor-1alpha-mediated invasion of breast carcinoma cells.

Abstract

Hypoxia-inducible factor-1alpha (HIF-1alpha) overexpression was shown to be associated with invasion and metastasis of tumors and tumor cell lines. The identification of molecular targets that contribute to HIF-1alpha-mediated invasion is under intensive investigation. We have analyzed the role of recepteur d'origine nantais (RON), a tyrosine kinase receptor for macrophage-stimulating protein (MSP) that plays a role in breast cancer cell invasion as one of the molecular targets of HIF-1alpha. Analysis of a panel of breast cancer cell lines indicated a correlation between HIF-1alpha and RON expression. Treatment of HIF-1alpha- and RON-positive breast cancer cells with HIF-1alpha inhibitor, echinomycin, led to the inhibition of HIF-1alpha activity and RON expression. We have identified HIF-1alpha binding site on the RON promoter. Chromatin immunoprecipitation analysis and site-directed mutagenesis of the RON promoter confirmed the binding of HIF-1alpha to RON promoter. HIF-1alpha inhibitor-, echinomycin-, or short hairpin RNA-mediated selective knockdown of HIF-1alpha or HIF-1alpha target RON tyrosine kinase abrogated RON gene expression, and the RON ligand macrophage-stimulating protein mediated invasion of breast cancer cells. Consequently, the data presented herein demonstrated RON as a novel molecular target of HIF-1alpha and suggest a potential therapeutic role for HIF-1alpha or RON tyrosine kinase inhibitors in the blockade of RON tyrosine kinase-mediated invasion of carcinoma cells.

• Authors: Amalraj Thangasamy, Jessica Rogge, Sudhakar Ammanamanchi
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 284 Issue 21 Pg. 14001-10 (May 22 2009) ISSN: 0021-9258 [Print] United States
• PMID: 19307182 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Cell Extracts
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Phosphoinositide-3 Kinase Inhibitors
• Proto-Oncogene Proteins
• RNA, Small Interfering
• macrophage stimulating protein
• Echinomycin
• Hepatocyte Growth Factor
• RON protein
• Receptor Protein-Tyrosine Kinases
• Extracellular Signal-Regulated MAP Kinases

Topics

• Breast Neoplasms (enzymology, genetics, pathology)
• Cell Extracts
• Cell Line, Tumor
• Echinomycin (pharmacology)
• Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors)
• Gene Expression Regulation, Neoplastic (drug effects)
• Gene Knockdown Techniques
• Hepatocyte Growth Factor (metabolism)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Neoplasm Invasiveness
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Promoter Regions, Genetic (genetics)
• Proto-Oncogene Proteins (metabolism)
• RNA, Small Interfering (metabolism)
• Receptor Protein-Tyrosine Kinases (antagonists & inhibitors, genetics, metabolism)