Radiation-induced exosomes promote oral squamous cell carcinoma progression via enhancing SLC1A5-glutamine metabolism

IF 2.7 3区医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE

Journal of Oral Pathology & Medicine Pub Date : 2024-05-27 DOI:10.1111/jop.13561

Rongchun Yang, Siyuan Zhang, Lixuan Wang, Yingyao Chen, Xiaobing Chen, Juan Xia, Xianyue Ren, Bin Cheng, Xijuan Chen

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引用次数: 0

Abstract

Background

Radiotherapy (RT) can drive cancer cells to enter a state of cellular senescence in which cells can secrete senescence-associated secretory phenotype (SASP) and produce small extracellular vesicles (sEVs) to interact with cells in the tumor microenvironment (TME). Tumor-derived sEVs that are taken up by recipient cells contribute to cancer cell metabolic plasticity, resistance to anticancer therapy, and adaptation to the TME. However, how radiation-induced sEVs support oral squamous cell carcinoma (OSCC) progression remains unclear.

Methods

Beta-galactosidase staining and SASP mRNA expression analysis were used to evaluate the senescence-associated activity of OSCC cells after irradiation. Nanoparticle tracking analysis was performed to identify radiation-induced sEVs. Liquid chromatography–tandem mass spectrometry (LC–MS) was used to explore changes in the levels of proteins in radiation-induced sEVs. Cell Counting Kit-8 and colony formation assays were performed to investigate the function of radiation-induced SASP and sEVs in vitro. A xenograft tumor model was established to investigate the functions of radiation-induced sEVs and V-9302 in vivo as well as the underlying mechanisms. Bioinformatics analysis was performed to determine the relationship between glutamine metabolism and OSCC recurrence.

Results

We determined that the radiation-induced SASP triggered OSCC cell proliferation. Additionally, radiation-induced sEVs exacerbated OSCC cell malignancy. LC–MS/MS and bioinformatics analyses revealed that SLC1A5, which is a cellular receptor that participates in glutamine uptake, was significantly enriched in radiation-induced sEVs. In vitro and in vivo, inhibiting SLC1A5 could block the oncogenic effects of radiation-induced sEVs in OSCC.

Conclusion

Radiation-induced sEVs might promote the proliferation of unirradiated cancer cells by enhancing glutamine metabolism; this might be a novel molecular mechanism underlying radiation resistance in OSCC patients.

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辐射诱导的外泌体通过增强SLC1A5-谷氨酰胺代谢促进口腔鳞状细胞癌的进展

背景：放疗（RT）可促使癌细胞进入细胞衰老状态，在这种状态下，细胞可分泌衰老相关分泌表型（SASP）并产生小细胞外囊泡（sEVs），与肿瘤微环境（TME）中的细胞相互作用。被受体细胞吸收的肿瘤衍生小泡有助于癌细胞的代谢可塑性、抗癌治疗的耐受性以及对肿瘤微环境的适应性。然而，辐射诱导的sEV如何支持口腔鳞状细胞癌（OSCC）的进展仍不清楚：方法：采用β-半乳糖苷酶染色和SASP mRNA表达分析评估OSCC细胞在辐照后的衰老相关活性。纳米粒子追踪分析用于识别辐射诱导的sEVs。液相色谱-串联质谱法（LC-MS）用于研究辐射诱导的sEVs中蛋白质水平的变化。为了研究辐射诱导的 SASP 和 sEVs 在体外的功能，进行了细胞计数试剂盒-8 和集落形成试验。建立了异种移植肿瘤模型，以研究辐射诱导的 sEVs 和 V-9302 在体内的功能及其内在机制。通过生物信息学分析确定谷氨酰胺代谢与 OSCC 复发之间的关系：结果：我们发现辐射诱导的 SASP 会引发 OSCC 细胞增殖。此外，辐射诱导的 sEVs 加剧了 OSCC 细胞的恶性程度。LC-MS/MS和生物信息学分析表明，参与谷氨酰胺摄取的细胞受体SLC1A5在辐射诱导的sEVs中显著富集。在体外和体内，抑制 SLC1A5 可阻断辐射诱导的 sEVs 对 OSCC 的致癌作用：结论：辐射诱导的sEVs可能会通过增强谷氨酰胺代谢来促进未受辐射癌细胞的增殖；这可能是OSCC患者耐辐射的一种新的分子机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Oral Pathology & Medicine 医学-病理学

CiteScore

5.90

自引率

6.10%

发文量

121

审稿时长

4-8 weeks

期刊介绍： The aim of the Journal of Oral Pathology & Medicine is to publish manuscripts of high scientific quality representing original clinical, diagnostic or experimental work in oral pathology and oral medicine. Papers advancing the science or practice of these disciplines will be welcomed, especially those which bring new knowledge and observations from the application of techniques within the spheres of light and electron microscopy, tissue and organ culture, immunology, histochemistry and immunocytochemistry, microbiology, genetics and biochemistry.