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SPINK4 modulates inhibition of glycolysis against colorectal cancer progression

Xiaodi Yang1, Sen Jiang2, Zhen Yuan1

  • 1Department of Oncology, Minhang Branch, Zhongshan Hospital, Fudan University, Shanghai, China; Key Laboratory of Whole-period Monitoring and Precise Intervention of Digestive Cancer (SMHC), Minhang Hospital and AHS, Fudan University, Shanghai, China.

Biomolecules & Biomedicine
|May 15, 2024
PubMed

Insights

Serine peptidase inhibitor, Kazal type 4 (SPINK4) is downregulated in colorectal cancer (CRC), inhibiting tumor growth and proliferation. SPINK4 acts as a key inhibitor of glycolytic metabolism, offering potential for CRC metabolic intervention.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Metabolism

Background:

  • Glycolysis dysregulation is linked to aggressive colorectal cancer (CRC) tumor activity.
  • Serine peptidase inhibitor, Kazal type 4 (SPINK4) is associated with CRC, but its role in glycolysis and gene expression is unclear.

Purpose of the Study:

  • To investigate the role of SPINK4 in colorectal cancer (CRC) progression, focusing on its impact on glycolysis, cell cycle, and apoptosis.
  • To analyze SPINK4 expression and its correlation with patient prognosis in CRC.

Main Methods:

  • Bioinformatic analysis of CRC datasets (GSE32323, GSE141174) to screen differentially expressed genes (DEGs) and analyze SPINK4 expression and prognosis.
  • In vitro studies using flow cytometry, western blotting, transwell assays, and qRT-PCR to assess SPINK4's effects on CRC cell proliferation, invasion, migration, apoptosis, cell cycle, and glycolysis.
  • In vivo xenograft models and histological/immunohistochemical analyses to evaluate SPINK4's impact on tumor development and expression patterns in CRC tissues.

Main Results:

  • SPINK4 expression was found to be downregulated in CRC tissues and correlated with poor patient prognosis.
  • SPINK4 overexpression inhibited CRC cell proliferation, invasion, and migration, induced G1 arrest, and promoted apoptosis.
  • SPINK4 overexpression reduced glycolytic activity, 2-Deoxy-D-glucose (2-DG) absorption, and modulated key glycolytic enzymes (HK2, GLUT1, LDHA, PKM2), significantly reducing tumor volume in vivo.
  • SPINK4 knockdown reversed these effects, promoting CRC progression.

Conclusions:

  • SPINK4 acts as a tumor suppressor in colorectal cancer by inhibiting proliferation, invasion, migration, and glycolysis.
  • SPINK4's downregulation in CRC suggests its potential as a prognostic biomarker.
  • SPINK4's role as a key inhibitor of glycolytic metabolism presents therapeutic opportunities for CRC intervention.

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