CKS2 可诱导自噬介导的谷胱甘肽代谢重编程,从而促进结肠癌的铁变态反应抵抗。

IF 6 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Leilei Yang, Chengfeng Fang, Jiaju Han, Yufeng Ren, Zaiping Yang, Lingyan Shen, Dinghai Luo, Ruili Zhang, Yan Chen, Shenkang Zhou
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引用次数: 0

摘要

背景:铁氧化是一种以脂质过氧化为特征的细胞死亡形式,在抑制肿瘤方面起着至关重要的作用,为癌症治疗提供了新的途径。以往的研究表明,高水平的细胞周期蛋白依赖性激酶亚基 2(CKS2)会促进各种癌症的进展。然而,结肠癌(CC)中 CKS2 与铁突变之间的潜在相互作用仍不清楚:方法:采用生物信息学和 RNA-seq 分析方法研究与铁突变信号通路相关的基因。采用定量反转录聚合酶链反应(qRT-PCR)和Western印迹(WB)评估了CKS2的表达。通过 CCK-8 试验、菌落形成试验、碘化丙啶(PI)染色、BODIPY 染色、DCFH-DA 染色和动物实验,评估了 CKS2 对 CC 细胞的体内外影响。此外,还利用透射电子显微镜(TEM)、免疫荧光(IF)检测、WB 实验和相关检测试剂盒研究了 CKS2 对自噬和谷胱甘肽(GSH)代谢的影响:结果:CC中CKS2表达升高,表明临床预后不佳。敲除 CKS2 能显著增强 Erastin 诱导的 CC 细胞铁凋亡,导致 GSH 代谢减少。相反,CKS2过表达则会产生相反的效果。从机理上讲,CKS2-诱导的自噬加强了GSH代谢,从而增强了CC细胞对铁变态反应的抵抗力。此外,抑制CKS2可通过下调GPX4的表达促进肿瘤的铁变态反应。此外,在体外和体内敲除CKS2都能有效增加索拉非尼诱导的铁变态反应:结论:CKS2通过调节体外和体内的GSH代谢抑制CC中的铁卟啉沉积。这些发现为以CKS2为靶点治疗CC提供了新的见解,并揭示了CC中的铁变态反应机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
CKS2 induces autophagy-mediated glutathione metabolic reprogramming to facilitate ferroptosis resistance in colon cancer.

Background: Ferroptosis, a form of cell death characterized by lipid peroxidation, plays a crucial role in tumor suppression, offering novel avenues for cancer therapy. Previous studies have indicated that high levels of cyclin-dependent kinase subunit 2 (CKS2) promote the progression of various cancers. However, the potential interplay between CKS2 and ferroptosis in colon cancer (CC) remains unclear.

Methods: Bioinformatics and RNA-seq analyses were employed to study genes associated with the ferroptosis signaling pathway. CKS2 expression was evaluated using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot (WB). The in vitro and in vivo effects of CKS2 on CC cells were assessed through the CCK-8 assay, colony formation assay, propidium iodide (PI) staining, BODIPY staining, DCFH-DA staining, and animal experiments. Additionally, the impact of CKS2 on autophagy and glutathione (GSH) metabolism was investigated using a transmission electron microscope (TEM), immunofluorescence (IF) assays, WB experiments, and relevant assay kits.

Results: CKS2 expression was elevated in CC, indicating a poor clinical outcome. Knockdown of CKS2 significantly enhanced Erastin-induced ferroptosis in CC cells, leading to reduced GSH metabolism. Conversely, CKS2 overexpression produced opposite effects. Mechanistically, CKS2-induced autophagy reinforced GSH metabolism, thereby increasing resistance to ferroptosis in CC cells. Furthermore, inhibiting CKS2 promoted tumor ferroptosis by downregulating GPX4 expression. Additionally, CKS2 knockdown effectively increased sorafenib-induced ferroptosis both in vitro and in vivo.

Conclusion: CKS2 suppresses ferroptosis in CC by modulating GSH metabolism in both in vitro and in vivo settings. These findings offer new insights into targeting CKS2 for CC treatment and shed light on the mechanism of ferroptosis in CC.

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来源期刊
Molecular Medicine
Molecular Medicine 医学-生化与分子生物学
CiteScore
8.60
自引率
0.00%
发文量
137
审稿时长
1 months
期刊介绍: Molecular Medicine is an open access journal that focuses on publishing recent findings related to disease pathogenesis at the molecular or physiological level. These insights can potentially contribute to the development of specific tools for disease diagnosis, treatment, or prevention. The journal considers manuscripts that present material pertinent to the genetic, molecular, or cellular underpinnings of critical physiological or disease processes. Submissions to Molecular Medicine are expected to elucidate the broader implications of the research findings for human disease and medicine in a manner that is accessible to a wide audience.
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