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Ref Type Journal Article
PMID (26772202)
Authors Chang HY, Chang TC, Huang WY, Lee CT, Yen CJ, Tsai YS, Tzai TS, Chen SH, Chow NH
Title RON Nuclear Translocation under Hypoxia Potentiates Chemoresistance to DNA Double-Strand Break-Inducing Anticancer Drugs.
Journal Molecular cancer therapeutics
Vol 15
Issue 2
Date 2016 Feb
URL
Abstract Text Tumor hypoxia is associated with radioresistance, chemoresistance, and metastasis, which eventually lead to cancer progression and a poor patient prognosis. RON [also known as macrophage-stimulating protein receptor (MST1R)] belongs to the c-MET [also known as hepatocyte growth factor receptor (HGFR)] receptor tyrosine kinase (RTK) superfamily. To identify the interaction partners of RON nuclear translocation in response to hypoxia, the nuclear extract of TSGH8301 bladder cancer cells was immunoprecipitated for tandem mass profiling analysis. Nuclear RON interacted with adenosine triphosphate (ATP)-dependent DNA helicase 2 (Ku70) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to activate nonhomologous end joining (NHEJ) DNA repair. The interaction was time dependent, extending 3 to 24 hours posthypoxia or until the components had been exposed to the chemotherapeutic drugs doxorubicin and epirubicin. Stable knockdown experiments in vitro suggest the importance of RON for the chemoresistance of cancer cells under hypoxia. In addition, the tyrosine kinase domain of nuclear RON is crucial for interaction with Ku70 under hypoxia. J82 cells transfected with RON showed a survival advantage in the presence of epirubicin and hypoxia. This suggests that nuclear RON activates NHEJ repair by interacting with Ku70/DNA-PKcs and inhibiting RON activity to increase cancer cell chemosensitivity. Mol Cancer Ther; 15(2); 276-86. ©2016 AACR.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
MST1R over exp urinary bladder cancer decreased response Epirubicin Preclinical - Cell culture Actionable In a preclinical study, MST1R (RON) over expression resulted in decreased sensitivity to Ellence (epirubicin) in bladder cancer cells under hypoxia in culture, resulting in increased cell survival (PMID: 26772202). 26772202
MST1R dec exp bladder carcinoma predicted - sensitive Doxorubicin Preclinical - Cell culture Actionable In a preclinical study, knockdown of MST1R (RON) increased sensitivity of a bladder carcinoma cell line to Adriamycin (doxirubicin) under hypoxia in culture, resulting in decreased cell survival (PMID: 26772202). 26772202
MST1R dec exp bladder carcinoma predicted - sensitive Epirubicin Preclinical - Cell culture Actionable In a preclinical study, knockdown of MST1R (RON) increased sensitivity of a bladder carcinoma cell line to Ellence (epirubicin) under hypoxia in culture, resulting in decreased cell survival (PMID: 26772202). 26772202