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

IF 8.2 2区生物学 Q1 CELL BIOLOGY Cell Communication and Signaling Pub Date : 2024-11-05 DOI:10.1186/s12964-024-01915-0

Hyun Jeong Seok, Jae Yeon Choi, Dong Hyeon Lee, Incheol Shin, In Hwa Bae

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引用次数: 0

Abstract

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.

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阿托莫西汀通过circATIC/miR-520d-5p/Notch2-Hey1轴抑制胶质母细胞瘤的放射抗性

背景：放疗后产生的抗药性与各种癌症治疗的失败直接相关，包括肿瘤坏死因子转移抑制剂（GBM）。由于克服放射抗性的机制尚未明确，因此有必要开发治疗放射抗性的诊断和治疗标记物。据报道，干性和 EMT 相关标记物的表达增加与放射抗性密切相关，因此目前正在研究开发针对这些因素的新药：方法：为了开发克服放射抗药性的抗癌药物，我们使用了一个已获美国食品及药物管理局批准的药物库。用每种药物处理具有放射抗性的GBM细胞后，通过qRT-PCR证实了干性和EMT相关标记物的表达，结果选择了阿托莫西汀（ATX）。实验证实，ATX治疗后，放射抗性诱导的细胞迁移、侵袭、球形成能力以及异种移植小鼠模型的肿瘤生长均受到抑制。利用 miRNA 预测工具，我们发现了靶向放射抗性关键因子 Notch2 和 Hey1 的 miR-520d-5p，并发现了靶向该 miRNA 的 circATIC，揭示了其与 ATX 的关系。我们利用荧光素酶报告实验证明了circATIC、miR-520d-5p、Notch2和Hey1因子之间的表达调控机制和信号转导机制。此外，通过使用患者血浆进行 qRT-PCR，证实了辐射、miR-520d-5p 和 circATIC 之间的相关性，从而在临床上验证了细胞水平的结果：结果：ATX通过调节circATIC/miR-520d-5p/Notch2-Hey1信号机制，在体外和体内使用耐放射的GBM细胞抑制恶性表型，显示出治疗放射耐药性的潜力：本研究揭示了ATX通过circATIC/miR-520d-5p/Notch2-Hey1信号通路抑制放射抗性。这些结果表明，ATX有可能成为克服癌症治疗中的一大挑战--放射抗性的新药，而在这一机制中发现的信号传导因子表明，ATX有可能成为诊断和治疗放射抗性的潜在靶点。

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来源期刊

Cell Communication and Signaling CELL BIOLOGY-

CiteScore

11.00

自引率

0.00%

发文量

180

期刊介绍： Cell Communication and Signaling (CCS) is a peer-reviewed, open-access scientific journal that focuses on cellular signaling pathways in both normal and pathological conditions. It publishes original research, reviews, and commentaries, welcoming studies that utilize molecular, morphological, biochemical, structural, and cell biology approaches. CCS also encourages interdisciplinary work and innovative models, including in silico, in vitro, and in vivo approaches, to facilitate investigations of cell signaling pathways, networks, and behavior. Starting from January 2019, CCS is proud to announce its affiliation with the International Cell Death Society. The journal now encourages submissions covering all aspects of cell death, including apoptotic and non-apoptotic mechanisms, cell death in model systems, autophagy, clearance of dying cells, and the immunological and pathological consequences of dying cells in the tissue microenvironment.