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Atomoxetine suppresses radioresistance in glioblastoma via circATIC/miR-520d-5p/Notch2-Hey1 axis
Hyun Jeong Seok1,2, Jae Yeon Choi1, Dong Hyeon Lee1
1Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea.
Background:
Resistance acquired after radiotherapy is directly related to the failure of various cancer treatments, including GBM. Because the mechanism for overcoming radioresistance has not yet been clearly identified, the development of diagnostic and therapeutic markers to treat radioresistance is necessary. Since increased expression of stemness- and EMT-related markers are reported to be closely correlated with radioresistance, research is underway to develop new drugs targeting these factors.
Methods:
To develop an anticancer drug that overcomes radioresistance, a library of drugs already approved by the FDA was used. After treating radioresistant GBM cells with each drug, the expression of stemness- and EMT-related markers was confirmed by qRT-PCR, and as a result, Atomoxetine (ATX) was selected. It was confirmed that radioresistance-induced cell migratory, invasive, sphere formation abilities, and tumor growth using a xenograft mouse model were suppressed upon ATX treatment. Using a miRNA prediction tool, we discovered miR-520d-5p, which targets Notch2 and Hey1, key factors in radioresistance, and discovered circATIC targeting this miRNA, revealing its relationship with ATX. We demonstrated the expression regulation mechanism and signaling mechanism between circATIC, miR-520d-5p, Notch2, and Hey1 factors using a luciferase reporter assay. In addition, the results at the cellular level were clinically verified by confirming the correlation between radiation, miR-520d-5p, and circATIC using patient plasma by qRT-PCR.
Results:
ATX showed potential as a treatment for radioresistance by suppressing the malignant phenotype by regulating the circATIC/miR-520d-5p/Notch2-Hey1 signaling mechanism in vitro and in vivo using radioresistant GBM cells.
Conclusions:
This study revealed that ATX suppresses radioresistance through the circATIC/miR-520d-5p/Notch2-Hey1 signaling pathway. These results showed the potential of ATX as a new drug that can overcome radioresistance, a major challenge in cancer treatment, and the signaling factors identified in this mechanism suggest the possibility of use as potential targets for the diagnosis and treatment of radioresistance.
Insights
Atomoxetine (ATX) overcomes radioresistance in glioblastoma by regulating the circATIC/miR-520d-5p/Notch2-Hey1 pathway. This study identifies ATX as a potential therapeutic agent and key signaling factors as diagnostic and therapeutic targets for radioresistant cancers.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Acquired resistance to radiotherapy is a major cause of treatment failure in cancers like glioblastoma (GBM).
- Mechanisms of radioresistance are not fully understood, necessitating new diagnostic and therapeutic markers.
- Increased stemness and EMT markers correlate with radioresistance, driving research into targeted therapies.
Purpose of the Study:
- To develop an anticancer drug capable of overcoming radioresistance in GBM.
- To identify novel therapeutic targets and diagnostic markers for radioresistant cancers.
Main Methods:
- Screened FDA-approved drugs against radioresistant GBM cells, selecting Atomoxetine (ATX) based on marker expression.
- Utilized qRT-PCR, xenograft mouse models, miRNA prediction, and luciferase reporter assays to elucidate the ATX mechanism.
- Validated findings in patient plasma to confirm clinical relevance of identified signaling pathway.
Main Results:
- ATX treatment suppressed migratory, invasive, and sphere formation abilities of radioresistant GBM cells, and reduced tumor growth in vivo.
- Identified a novel pathway involving circATIC, miR-520d-5p, Notch2, and Hey1, regulated by ATX.
- Confirmed the circATIC/miR-520d-5p/Notch2-Hey1 pathway's role in ATX-mediated suppression of radioresistance.
Conclusions:
- Atomoxetine (ATX) effectively overcomes radioresistance in glioblastoma by modulating the circATIC/miR-520d-5p/Notch2-Hey1 signaling pathway.
- ATX demonstrates potential as a novel therapeutic agent for overcoming radioresistance.
- The identified signaling pathway components serve as promising targets for diagnosing and treating radioresistant cancers.
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