Journal Article

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

Wang, Bei, Liu, Gui, Wang, Zixuan, Jiang, Zhenyuan, Geng, Wei, Zhou, Zini, Zheng, Mingyue

2025

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: 6-phosphogluconate dehydrogenase / AMP-Activated Protein Kinases - metabolism / Animals / Apoptosis - drug effects / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cancer therapies / Cell cycle / Cell growth / Cell Line, Tumor / Cell proliferation / Cell Proliferation - drug effects / Dehydrogenases / Development and progression / Enzymes / Esophageal cancer / Esophageal carcinoma / Esophageal Neoplasms - drug therapy / Esophageal Neoplasms - genetics / Esophageal Neoplasms - metabolism / Esophageal Neoplasms - pathology / Esophageal squamous cell carcinoma / Esophageal Squamous Cell Carcinoma - drug therapy / Esophageal Squamous Cell Carcinoma - genetics / Esophageal Squamous Cell Carcinoma - metabolism / Esophageal Squamous Cell Carcinoma - pathology / Female / Gene Expression Regulation, Neoplastic - drug effects / Glycolysis / Growth / Health aspects / Humans / Kinases / Male / Medical prognosis / Metabolism / Metastasis / Metformin / Metformin - pharmacology / Mice / Mice, Nude / Molecular modelling / Oncology / Oxidative stress / Pentose phosphate pathway / Phosphates / Phosphogluconate dehydrogenase (decarboxylating) / Phosphogluconate Dehydrogenase - antagonists & inhibitors / Phosphogluconate Dehydrogenase - genetics / Phosphogluconate Dehydrogenase - metabolism / Phosphorylation / Physcion / Physiological aspects / Proteins / Signal Transduction - drug effects / Squamous cell carcinoma / Survival analysis / Therapeutic targets / TOR protein / TOR Serine-Threonine Kinases - metabolism / Tumor cells / Tumors / Xenograft Model Antitumor Assays