Ursolic acid enhances radiosensitivity in esophageal squamous cell carcinoma by modulating p53/SLC7A11/GPX4 pathway-mediated ferroptosis.

IF 2.6 4区医学 Q2 PHARMACOLOGY & PHARMACY Toxicon Pub Date : 2025-01-07 DOI:10.1016/j.toxicon.2025.108233

Nuran Bedolla, Linyu Liu, Xueting Liu, Qiuxian Xie, Yanli Ren

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Abstract

Background: Radiotherapy is essential for the management of esophageal squamous cell carcinoma (ESCC). However, ESCC cells are highly susceptible to developing resistance to radiotherapy, leading to poor prognosis. Ursolic acid (UA) is a herbal monomer, has multiple medicinal benefits like anti-tumor. The impact of UA on the sensitivity of ESCC cells to radiotherapy is currently unclear.

Methods: The impact of UA and ionizing radiation (IR) on the viability of TE-1 and KYSE30 cells was assessed by the MTT assay. EdU staining, flow cytometry, clone formation, Wound healing and Transwell assay detected the biological properties of ESCC cells. FerroOrange, DCFH-DA, and kits to detect the influences of UA and/or IR treatment on cellular ferroptosis. The levels of p53/solute carrier family 7a member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) pathway proteins were detected by Western blot. Additionally, a subcutaneous graft tumor model was constructed in nude mice.

Results: 10 μM UA reduced the viability and induced death of ESCC cells. UA enhanced the impacts of IR by suppressing cell proliferation, migration and invasion, inducing cell death, and causing cell cycle arrest. Ferroptosis inhibitor impaired the inhibitory impacts of UA and IR on the biological properties of ESCC cells. The combination of UA and IR led to ferroptosis through the modulation of the p53/SLC7A11/GPX4 pathway, and UA enhanced the responsiveness of ESCC cells to IR both in vitro and in vivo.

Conclusion: UA inhibits the malignant biological behavior of ESCC by modulating ferroptosis through the p53/SLC7A11/GPX4 pathway, and enhances the sensitivity of ESCC cells to IR.

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熊果酸通过调节p53/SLC7A11/GPX4通路介导的铁下垂增强食管鳞状细胞癌的放射敏感性。

背景：放疗对于食管鳞状细胞癌（ESCC）的治疗至关重要。然而，ESCC细胞极易对放疗产生耐药性，导致预后不良。熊果酸（UA）是一种草药单体，具有抗肿瘤等多种药用价值。UA对ESCC细胞放疗敏感性的影响目前尚不清楚。方法：采用MTT法观察UA和IR对TE-1和KYSE30细胞活力的影响。EdU染色、流式细胞术、克隆形成、创面愈合和Transwell实验检测ESCC细胞的生物学特性。铁橙，DCFH-DA和试剂盒检测UA和/或IR处理对细胞铁下垂的影响。Western blot检测p53/溶质载体家族7a成员11 (SLC7A11)/谷胱甘肽过氧化物酶4 （GPX4）通路蛋白水平。建立裸鼠皮下移植瘤模型。结果：10 μM UA降低ESCC细胞活力，诱导细胞死亡。UA通过抑制细胞增殖、迁移和侵袭、诱导细胞死亡和引起细胞周期阻滞来增强IR的影响。铁下垂抑制剂削弱了UA和IR对ESCC细胞生物学特性的抑制作用。UA和IR联合作用通过调节p53/SLC7A11/GPX4通路导致铁凋亡，UA在体外和体内均增强了ESCC细胞对IR的反应性。结论：UA通过p53/SLC7A11/GPX4通路调控铁凋亡，抑制ESCC的恶性生物学行为，增强ESCC细胞对IR的敏感性。

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来源期刊

Toxicon 医学-毒理学

CiteScore

4.80

自引率

10.70%

发文量

358

审稿时长

68 days

期刊介绍： Toxicon has an open access mirror Toxicon: X, sharing the same aims and scope, editorial team, submission system and rigorous peer review. An introductory offer Toxicon: X - full waiver of the Open Access fee. Toxicon''s "aims and scope" are to publish: -articles containing the results of original research on problems related to toxins derived from animals, plants and microorganisms -papers on novel findings related to the chemical, pharmacological, toxicological, and immunological properties of natural toxins -molecular biological studies of toxins and other genes from poisonous and venomous organisms that advance understanding of the role or function of toxins -clinical observations on poisoning and envenoming where a new therapeutic principle has been proposed or a decidedly superior clinical result has been obtained. -material on the use of toxins as tools in studying biological processes and material on subjects related to venom and antivenom problems. -articles on the translational application of toxins, for example as drugs and insecticides -epidemiological studies on envenoming or poisoning, so long as they highlight a previously unrecognised medical problem or provide insight into the prevention or medical treatment of envenoming or poisoning. Retrospective surveys of hospital records, especially those lacking species identification, will not be considered for publication. Properly designed prospective community-based surveys are strongly encouraged. -articles describing well-known activities of venoms, such as antibacterial, anticancer, and analgesic activities of arachnid venoms, without any attempt to define the mechanism of action or purify the active component, will not be considered for publication in Toxicon. -review articles on problems related to toxinology. To encourage the exchange of ideas, sections of the journal may be devoted to Short Communications, Letters to the Editor and activities of the affiliated societies.