肿瘤相关缺氧生物标志物碳酸酐酶IX糖基化改变的功能后果。

IF 2 4区 医学 Q3 ONCOLOGY
Magdalena Baratova, Lucia Skvarkova, Maria Bartosova, Lenka Jelenska, Miriam Zatovicova, Barbora Puzderova, Ivana Kajanova, Lucia Csaderova, Silvia Pastorekova, Eliska Svastova
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引用次数: 0

摘要

糖基化是蛋白质的翻译后修饰,影响许多细胞功能。越来越多的证据证实,异常糖基化参与病理生理过程,包括肿瘤的发生和进展。碳酸酐酶IX (carbon anhydrase IX, CAIX)是一种跨膜蛋白,其表达在缺氧肿瘤中被强烈诱导,这使其成为抗肿瘤治疗的一个有吸引力的靶点。CAIX通过其催化活性促进细胞内pH稳态的维持,这与细胞外pH酸化促进肿瘤细胞更具侵袭性的表型有关。CAIX参与破坏细胞-细胞接触和局灶黏附过程也有助于肿瘤进展。先前的研究表明,CAIX可以用n -聚糖、o -聚糖和糖胺聚糖(GAG)进行修饰。尽管如此,糖基化对CAIX功能的影响尚未完全阐明。通过制备稳定转染的表达CAIX突变形式的细胞,无法在其定义的位点结合聚糖,我们试图阐明聚糖结构在CAIX功能中的作用。所有三种制备的突变体都表现出对胶原的粘附性降低。通过表面等离子体共振,我们证实了CAIX与胶原蛋白之间的直接结合。缺乏CAIX糖胺聚糖修饰的细胞也表现出迁移和侵袭减少,表明CAIX糖胺聚糖参与了这些过程。CAIX分子GAG成分缺失对信号通路的影响分析显示,缺氧培养的细胞c-Jun、p38α激酶、黏附激酶磷酸化水平降低,热休克蛋白60水平降低。表达CAIX而不表达GAG的细胞表现出代谢生成增加和细胞外pH酸化增加。我们还观察到缺氧炎症环境下CAIX GAG聚糖的减少,病理生理条件反映了体内肿瘤微环境。了解聚糖参与癌症治疗可能靶点的特征和功能,如细胞表面定位的CAIX,可以改善治疗,因为许多药物靶向蛋白质的聚糖部分。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Functional consequences of altered glycosylation of tumor-associated hypoxia biomarker carbonic anhydrase IX.

Glycosylation is a posttranslational modification of proteins affecting numerous cellular functions. A growing amount of evidence confirms that aberrant glycosylation is involved in pathophysiological processes, including tumor development and progression. Carbonic anhydrase IX (CAIX) is a transmembrane protein whose expression is strongly induced in hypoxic tumors, which makes it an attractive target for anti-tumor therapy. CAIX facilitates the maintenance of intracellular pH homeostasis through its catalytic activity, which is linked with extracellular pH acidification promoting a more aggressive phenotype of tumor cells. The involvement of CAIX in destabilizing cell-cell contacts and the focal adhesion process also contributes to tumor progression. Previous research shows that CAIX is modified with N-glycans, O-glycans, and glycosaminoglycans (GAG). Still, the impact of glycosylation on CAIX functions has yet to be fully elucidated. By preparing stably transfected cells expressing mutated forms of CAIX, unable to bind glycans at their defined sites, we have attempted to clarify the role of glycan structures in CAIX functions. All three types of prepared mutants exhibited decreased adhesion to collagen. By surface plasmon resonance, we proved direct binding between CAIX and collagen. Cells lacking glycosaminoglycan modification of CAIX also showed reduced migration and invasion, indicating CAIX glycosaminoglycans' involvement in these processes. Analysis of signaling pathways affected by the loss of GAG component from CAIX molecule revealed decreased phosphorylation of c-Jun, of p38α kinase, focal adhesion kinase, and reduced level of heat shock protein 60 in cells cultured in hypoxia. Cells expressing CAIX without GAG exhibited increased metabolon formation and increased extracellular pH acidification. We also observed reduced CAIX GAG glycans in the inflammatory environment in hypoxia, pathophysiological conditions reflecting in vivo tumor microenvironment. Understanding the glycan involvement in the characteristics and functions of possible targets of cancer treatment, such as cell surface localized CAIX, could improve the therapy, as many drugs target glycan parts of a protein.

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来源期刊
Neoplasma
Neoplasma 医学-肿瘤学
CiteScore
5.40
自引率
0.00%
发文量
238
审稿时长
3 months
期刊介绍: The journal Neoplasma publishes articles on experimental and clinical oncology and cancer epidemiology.
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