2. Academic Validation
  3. Inhibition of 6-phosphogluconate dehydrogenase suppresses esophageal squamous cell carcinoma growth and enhances the anti-tumor effects of metformin via the AMPK/mTOR pathway

Inhibition of 6-phosphogluconate dehydrogenase suppresses esophageal squamous cell carcinoma growth and enhances the anti-tumor effects of metformin via the AMPK/mTOR pathway

  • Mol Cancer. 2025 Mar 26;24(1):97. doi: 10.1186/s12943-025-02302-0.
Bei Wang # 1 2 3,  Zixuan Wang # 4 5,  Zini Zhou 6 4,  Gui Liu 6 7,  Zhenyuan Jiang 4 5,  Mingyue Zheng 2 3,  Wei Geng 8 9 10 11
Affiliations

Affiliations

  • 1 Yancheng Key Laboratory of Molecular Epigenetics, The First people's Hospital of Yancheng, The Yancheng Clinical College of Xuzhou Medical University, 66 South People's Road, Yancheng, 224000, Jiangsu, China.
  • 2 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, 210023, Jiangsu, China.
  • 3 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
  • 4 Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, China.
  • 5 Department of Radiotherapy, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, 42 Baizi Pavilion, Nanjing, 210009, Jiangsu, China.
  • 6 Department of Radiotherapy, The First people's Hospital of Yancheng, The Yancheng Clinical College of Xuzhou Medical University, 66 South People's Road, Yancheng, 224000, Jiangsu, China.
  • 7 School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China.
  • 8 Yancheng Key Laboratory of Molecular Epigenetics, The First people's Hospital of Yancheng, The Yancheng Clinical College of Xuzhou Medical University, 66 South People's Road, Yancheng, 224000, Jiangsu, China. weihuo2001@163.com.
  • 9 Department of Radiotherapy, The First people's Hospital of Yancheng, The Yancheng Clinical College of Xuzhou Medical University, 66 South People's Road, Yancheng, 224000, Jiangsu, China. weihuo2001@163.com.
  • 10 Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, China. weihuo2001@163.com.
  • 11 School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China. weihuo2001@163.com.
  • # Contributed equally.
PMID: 40140842 DOI: 10.1186/s12943-025-02302-0
Abstract

Metabolic reprogramming plays a pivotal role in the development and progression of tumors. Tumor cells rely on glycolysis as their primary energy production pathway and effectively utilize biomolecules generated by the pentose phosphate pathway (PPP) for efficient biosynthesis. However, the role of 6-phosphogluconate dehydrogenase (6PGD), a crucial enzyme in the PPP, remains unexplored in esophageal squamous cell carcinoma (ESCC). In this study, we observed a significant upregulation of 6PGD expression in ESCC tissues, which correlated with an unfavorable prognosis among patients. The experiments demonstrated that knockdown of 6PGD induces oxidative stress and suppresses ESCC cell proliferation. Mechanistically, this is achieved through AMPK activation and subsequent inhibition of downstream mTOR phosphorylation. Moreover, physcion has been found to inhibit 6PGD activity and exert its anti-ESCC effect via the AMPK/mTOR pathway. Subsequently, we conducted both in vitro and in vivo experiments to validate the Anticancer efficacy of combining metformin, an AMPK Activator, with physcion. The results demonstrated a significantly enhanced inhibition of ESCC growth. This study elucidates the impact of 6PGD on ESCC cell proliferation along with its underlying molecular mechanisms, highlighting its potential as a therapeutic target for ESCC. Furthermore, we investigated a novel approach for improved anti-tumor therapy involving physcion and metformin. These findings will contribute new insights to clinical treatment strategies for ESCC while providing a theoretical foundation for developing molecular targeted therapies.

Keywords

6-phosphogluconate dehydrogenase; Esophageal squamous cell carcinoma; Metformin; Pentose phosphate pathway; Physcion.

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