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Updated: Nov 6, 2025
Development of Compendium for Esophageal Squamous Cell Carcinoma
Published on: April 12, 2024
Identification of PDHX as a metabolic target for esophageal squamous cell carcinoma
Jun Inoue1, Masahiro Kishikawa1,2, Hitoshi Tsuda3
1Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
Abstract:
The metabolism in tumors is reprogrammed to meet its energetic and substrate demands. However, this metabolic reprogramming creates metabolic vulnerabilities, providing new opportunities for cancer therapy. Metabolic vulnerability as a therapeutic target in esophageal squamous cell carcinoma (ESCC) has not been adequately clarified. Here, we identified pyruvate dehydrogenase (PDH) component X (PDHX) as a metabolically essential gene for the cell growth of ESCC. PDHX expression was required for the maintenance of PDH activity and the production of ATP, and its knockdown inhibited the proliferation of cancer stem cells (CSCs) and in vivo tumor growth. PDHX was concurrently upregulated with the CD44 gene, a marker of CSCs, by co-amplification at 11p13 in ESCC tumors and these genes coordinately functioned in cancer stemness. Furthermore, CPI-613, a PDH inhibitor, inhibited the proliferation of CSCs in vitro and the growth of ESCC xenograft tumors in vivo. Thus, our study provides new insights related to the development of novel therapeutic strategies for ESCC by targeting the PDH complex-associated metabolic vulnerability.
Insights
Pyruvate dehydrogenase (PDH) component X (PDHX) is essential for esophageal squamous cell carcinoma (ESCC) growth. Targeting PDHX and its associated metabolic vulnerability offers a promising therapeutic strategy for ESCC.
Area of Science:
- Oncology
- Cancer Metabolism
- Molecular Biology
Background:
- Tumor metabolism is reprogrammed for growth, creating vulnerabilities exploitable for cancer therapy.
- Therapeutic targeting of metabolic vulnerabilities in esophageal squamous cell carcinoma (ESCC) remains underexplored.
Purpose of the Study:
- To identify and characterize metabolic vulnerabilities in ESCC.
- To investigate the role of pyruvate dehydrogenase (PDH) component X (PDHX) in ESCC progression and its potential as a therapeutic target.
Main Methods:
- Gene expression analysis and knockdown experiments to assess PDHX function in ESCC cells.
- In vitro and in vivo assays to evaluate the impact of PDHX inhibition on cancer stem cells (CSCs) and tumor growth.
- Analysis of gene co-amplification and functional correlation with CSC markers.
Main Results:
- PDHX was identified as a key metabolic gene essential for ESCC cell growth, maintaining PDH activity and ATP production.
- PDHX knockdown inhibited CSC proliferation and in vivo tumor growth.
- PDHX and CD44 (a CSC marker) were co-amplified and functionally coordinated in ESCC stemness.
- CPI-613, a PDH inhibitor, demonstrated efficacy against ESCC CSCs and xenograft tumors.
Conclusions:
- PDHX is a critical metabolic vulnerability in ESCC.
- Targeting the PDH complex, via PDHX inhibition, presents a novel therapeutic avenue for ESCC treatment.
- The findings offer new insights for developing targeted therapies against ESCC metabolic vulnerabilities.
