Atomoxetine suppresses radioresistance in glioblastoma via circATIC/miR-520d-5p/Notch2-Hey1 axis.

Autor: Seok HJ; Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea.; Department of Life Science, Hanyang University, Seoul, Republic of Korea., Choi JY; Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea., Lee DH; Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea., Shin I; Department of Life Science, Hanyang University, Seoul, Republic of Korea., Bae IH; Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea. ihbae@kirams.re.kr.
Jazyk: angličtina
Zdroj: Cell communication and signaling : CCS [Cell Commun Signal] 2024 Nov 05; Vol. 22 (1), pp. 532. Date of Electronic Publication: 2024 Nov 05.
DOI: 10.1186/s12964-024-01915-0
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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