RON nuclear translocation under hypoxia potentiated chemoresistance to DNA double-strand break-inducing anti-cancer drugs

Tumor hypoxia is associated with radioresistance, chemoresistance, and metastasis, which eventually lead to cancer progression and a poor patient prognosis. RON (aka macrophage-stimulating protein receptor [MST1R]) belongs to the c-MET (aka 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 (Ku-70) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to activate non-homologous end-joining (NHEJ) DNA repair. The interaction was time-dependent, extending 3-24 h post-hypoxia 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.

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