RON nuclear translocation under hypoxia potentiates chemoresistance to DNA double-strand break-inducing anticancer drugs

Hong Yi Chang, Ting Chia Chang, Wen Ya Huang, Chung Ta Lee, Chia Jui Yen, Yuh Shyan Tsai, Tzong Shin Tzai, Shu Hui Chen, Nan Haw Chow

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

Tumor hypoxia is associated with radioresistance, chemoresistance, and metastasis, which eventually lead to cancer progression and a poor patient prognosis. RON [also known as macrophagestimulating 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.

Original languageEnglish
Pages (from-to)276-286
Number of pages11
JournalMolecular Cancer Therapeutics
Volume15
Issue number2
DOIs
Publication statusPublished - 2016 Feb

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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