2. Academic Validation
  3. CDK5 promotes apoptosis and attenuates chemoresistance in gastric cancer via E2F1 signaling

CDK5 promotes apoptosis and attenuates chemoresistance in gastric cancer via E2F1 signaling

  • Cancer Cell Int. 2023 Nov 21;23(1):286. doi: 10.1186/s12935-023-03112-4.
Long-Long Cao # 1 2 3,  Yu-Kai Wu # 1 2 3,  Tong-Xin Lin # 1 2 3,  Mi Lin # 1 2 3,  Yu-Jing Chen # 1 2 3,  Ling-Qian Wang 1 2 3,  Jia-Bin Wang 1 2 3,  Jian-Xian Lin 1 2 3,  Jun Lu 1 2 3,  Qi-Yue Chen 1 2 3,  Ru-Hong Tu 1 2 3,  Ze-Ning Huang 1 2 3,  Ju-Li Lin 1 2 3,  Hua-Long Zheng 1 2 3,  Jian-Wei Xie 1 2 3,  Ping Li 1 2 3,  Chang-Ming Huang 4 5 6,  Chao-Hui Zheng 7 8 9
Affiliations

Affiliations

  • 1 Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, Fujian Province, 350001, China.
  • 2 Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China.
  • 3 Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China.
  • 4 Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, Fujian Province, 350001, China. hcmlr2002@163.com.
  • 5 Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China. hcmlr2002@163.com.
  • 6 Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China. hcmlr2002@163.com.
  • 7 Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, Fujian Province, 350001, China. wwkzch@163.com.
  • 8 Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China. wwkzch@163.com.
  • 9 Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China. wwkzch@163.com.
  • # Contributed equally.
PMID: 37990321 DOI: 10.1186/s12935-023-03112-4
Abstract

Background: Chemoresistance is a major clinical challenge that leads to tumor metastasis and poor clinical outcome. The mechanisms underlying gastric Cancer resistance to chemotherapy are still unclear.

Methods: We conducted bioinformatics analyses of publicly available patient datasets to establish an apoptotic phenotype and determine the key pathways and clinical significance. In vitro cell models, in vivo mouse models, and numerous molecular assays, including western blotting, qRT-PCR, immunohistochemical staining, and coimmunoprecipitation assays were used to clarify the role of factors related to Apoptosis in gastric Cancer in this study. Differences between datasets were analyzed using the Student's t-test and two-way ANOVA; survival rates were estimated based on Kaplan-Meier analysis; and univariate and multivariate COX proportional hazards models were used to evaluate prognostic factors.

Results: Bulk transcriptomic analysis of gastric Cancer samples established an apoptotic phenotype. Proapoptotic tumors were enriched for DNA repair and immune inflammatory signaling and associated with improved prognosis and chemotherapeutic benefits. Functionally, cyclin-dependent kinase 5 (CDK5) promoted Apoptosis of gastric Cancer cells and sensitized cells and mice to oxaliplatin. Mechanistically, we demonstrate that CDK5 stabilizes DP1 through direct binding to DP1 and subsequent activation of E2F1 signaling. Clinicopathological analysis indicated that CDK5 depletion correlated with poor prognosis and chemoresistance in human gastric tumors.

Conclusion: Our findings reveal that CDK5 promotes cell Apoptosis by stabilizing DP1 and activating E2F1 signaling, suggesting its potential role in the prognosis and therapeutic decisions for patients with gastric Cancer.

Keywords

Apoptosis; CDK5; Chemoresistance; Gastric cancer.

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