RON Nuclear Translocation under Hypoxia Potentiates Chemoresistance to DNA Double-Strand Break-Inducing Anticancer Drugs.
نویسندگان
چکیده
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.
منابع مشابه
The study of dose gamma rays of 192Ir source on DNA single strand break (SSB) and DNA double strand break (DSB) in soft tissue phantom
Introduction: Passage of ionizing radiation through the organs of living creatures develops clusters of damaged nucleotides inside the DNA rounds. 192Ir Gamma source is one of the most widely used sources in brachytherapy of cervical and prostate cancer. Thus, in this research, we investigated the flux of photons and its resulting secondary electrons, the single-strand break (S...
متن کاملG9a inhibition potentiates the anti-tumour activity of DNA double-strand break inducing agents by impairing DNA repair independent of p53 status
Cancer cells often exhibit altered epigenetic signatures that can misregulate genes involved in processes such as transcription, proliferation, apoptosis and DNA repair. As regulation of chromatin structure is crucial for DNA repair processes, and both DNA repair and epigenetic controls are deregulated in many cancers, we speculated that simultaneously targeting both might provide new opportuni...
متن کاملThe DNA double-stranded break repair protein endo-exonuclease as a therapeutic target for cancer.
DNA repair mechanisms are crucial for the maintenance of genomic stability and are emerging as potential therapeutic targets for cancer. In this study, we report that the endo-exonuclease, a protein involved in the recombination repair process of the DNA double-stranded break pathway, is overexpressed in a variety of cancer cells and could represent an effective target for developing anticancer...
متن کاملAcetylation: a novel link between double-strand break repair and autophagy.
Histone deacetylase (HDAC) inhibitors are clinically relevant because they are used as anticancer drugs. Recent evidence sheds light on an intriguing connection among the DNA damage response (DDR), protein acetylation, and autophagy. HDAC inhibitors have been shown to counteract key steps in the cellular response to double-strand break formation by affecting checkpoint activation, homologous re...
متن کاملEvaluating Gamma-H2AX Expression as a Biomarker of DNA Damage after X-ray in Angiography Patients
Objective: Coronary heart disease (CHD) is one of the most common diseases. Coronary angiography (CAG) is an important apparatus used to diagnose and treat this disease. Since angiography is performed through exposure to ionizing radiation, it can cause harmful effects induced by double-stranded breaks in DNA which is potentially life-threatening damage. The aim of the present study is to inves...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Molecular cancer therapeutics
دوره 15 2 شماره
صفحات -
تاریخ انتشار 2016