2. Academic Validation
  3. CKS2 induces autophagy-mediated glutathione metabolic reprogramming to facilitate ferroptosis resistance in colon cancer

CKS2 induces autophagy-mediated glutathione metabolic reprogramming to facilitate ferroptosis resistance in colon cancer

  • Mol Med. 2024 Nov 15;30(1):219. doi: 10.1186/s10020-024-00979-5.
Leilei Yang # 1 2,  Chengfeng Fang # 1,  Jiaju Han 1,  Yufeng Ren 1,  Zaiping Yang 3,  Lingyan Shen 4,  Dinghai Luo 4,  Ruili Zhang 5 6,  Yan Chen 7,  Shenkang Zhou 8 9
Affiliations

Affiliations

  • 1 Department of Gastrointestinal Surgery, Taizhou Hospital, Wenzhou Medical University, No.105 Westgate Street, Linhai, 317000, China.
  • 2 Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Linhai, 317000, China.
  • 3 Department of Anaesthesia, Taizhou Hospital, Wenzhou Medical University, Linhai, 317000, China.
  • 4 Department of Gastroenterology, Taizhou Hospital, Wenzhou Medical University, Linhai, 317000, China.
  • 5 Department of Gastrointestinal Surgery, Taizhou Hospital, Wenzhou Medical University, No.105 Westgate Street, Linhai, 317000, China. zhangrl@enzemed.com.
  • 6 Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Linhai, 317000, China. zhangrl@enzemed.com.
  • 7 Department of Family-oriented wards, Taizhou Hospital, Wenzhou Medical University, No.105 Westgate Street, Linhai, 317000, China. chenyan@enzemed.com.
  • 8 Department of Gastrointestinal Surgery, Taizhou Hospital, Wenzhou Medical University, No.105 Westgate Street, Linhai, 317000, China. tzyywcwk@163.com.
  • 9 Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Linhai, 317000, China. tzyywcwk@163.com.
  • # Contributed equally.
PMID: 39548421 DOI: 10.1186/s10020-024-00979-5
Abstract

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.

Keywords

Autophagy; Colon cancer; Cyclin-dependent kinase subunit 2; Ferroptosis; Glutathione metabolism.

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