6-Phosphogluconate dehydrogenase inhibition arrests growth and induces apoptosis in gastric cancer via AMPK activation and oxidative stress

Sep 24, 2026

Poor outcomes in advanced gastric cancer necessitate alternative therapeutic strategies. 6-Phosphogluconate dehydrogenase (6-PGDH), an enzyme driving the oxidative pentose phosphate pathway, is evaluated as a therapeutic target. Gastric cancer tissues show aberrantly elevated 6-PGDH expression and activity. Two independent shRNAs suppress 6-PGDH, reducing growth and enhancing sensitivity to 5-fluorouracil. Mechanistically, inhibition disrupts lipid biosynthesis and redox homeostasis, activates AMPK-related stress signaling, and promotes apoptosis, validated in a xenograft mouse model.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages11

Reading Time28 min

AccessFree to download

Introduction

Gastric cancer treatment and chemoresistance

Oxidative pentose phosphate pathway and 6-PGDH

Materials and methods

Tissue specimens and cell culture

Immunohistochemistry and western blot analysis

Research Article Cheng Chen\# , Pan Du\# , Zhenguo Zhang*, Di Bao* 6-Phosphogluconate dehydrogenase inhibition arrests growth and induces apoptosis in gastric cancer via AMPK activation and oxidative stress [https://doi.org/10.1515/biol](https://doi.org/10.1515/biol-2022-0514)[-](https://doi.org/10.1515/biol-2022-0514)[2022](https://doi.org/10.1515/biol-2022-0514)[-](https://doi.org/10.1515/biol-2022-0514)[0514](https://doi.org/10.1515/biol-2022-0514) received May 29, 2022; accepted September 21, 2022 Abstract: Poor outcomes in advanced gastric cancer necessitate alternative therapeutic strategies. 6-Phosphogluconate dehydrogenase (6-PGDH), an enzyme that catalyzes the decarboxylation step in the oxidative pentose phosphate pathway, has been identiﬁed as a promising therapeutic target in many cancers. In this study, we systematically investigated the expression and function of 6-PGDH in gastric cancer. We found that 6-PGDH expression and activity were aberrantly elevated in gastric cancer tissues compared to their adjacent normal tissues. 6-PGDH knockdown using two independent shRNAs resulted in minimal 6-PGDH levels and activity, decreased growth, and enhanced gastric cancer cell sensitivity to 5-ﬂurorouracil. However, 6-PGDH knockdown did not aﬀect the cancer cells. Mechanistic studies showed that 6-PGDH inhibition disrupted lipid biosynthesis and redox homeostasis in gastric cancer, inhibited growth, and induced apoptosis. Notably, the in vitro ﬁndings were validated using an in vivo gastric cancer xenograft mouse model. This study established that 6-PGDH is broadly elevated in gastric cancer patients and that 􀀁􀀁 \# These two authors contributed to this work equally and are coﬁrst authors. 􀀁􀀁 * Corresponding author: Zhenguo Zhang, Department of Gastroenterology, Xiangyang Central Hospital, Aﬃliated Hospital of Hubei University of Arts and Sciences, Xiangyang 441021, China, e-mail: [xhkzzg@163.com](xhkzzg@163.com) * Corresponding author: Di Bao, Department of Oncology, Xiangyang Central Hospital, Aﬃliated Hospital of Hubei University of Arts and Sciences, Xiangyang 441021, China; Institute of Oncology, Hubei University of Arts and Science, Xiangyang 441021, China, e-mail: [raro0403@sina.com](raro0403@sina.com) Cheng Chen, Pan Du: Department of Oncology, Xiangyang Central Hospital, Aﬃliated Hospital of Hubei University of Arts and Sciences, Xiangyang 441021, China; Institute of Oncology, Hubei University of Arts and Science, Xiangyang 441021, China 6-PGDH inhibition can sensitize gastric cancer cells in response to chemotherapy. Keywords: gastric cancer, 6-PGDH, redox homeostasis, AMPK, lipid biosynthesis 1 Introduction Gastric cancer is the second most common cause of cancer-related death worldwide [1] . Treatment options for patients with gastric cancer include gastrectomy and chemotherapy [2]. 5-Flurorouracil (5-FU), alone or in combination with other conventional therapies, is the standard chemotherapy regimen. However, resistance, either acquired or primary, is the main cause of treatment failure [3]. The mechanisms of gastric cancer pathogenesis and chemoresistance are not clear and rely on multiple factors, such as deregulation of developmental pathways and cancer stem cell signaling (Wnt/β-catenin, Hedgehog, Notch, STAT3, and epithelial–mesenchymal transition)[4,5]. Recent studies have suggested altering the biosynthetic metabolism in gastric cancer, including anabolic biosynthesis and redox homeostasis, which might represent a promising therapeutic target. Reduced levels of nicotinamide adenine dinucleotide phosphate (NADPH) is critical for redox defense and is the driving force of most biosynthetic enzymatic reactions, including DNA and lipids [6] . NADPH production is mediated by glutamine metabolism and the oxidative pentose phosphate pathway (PPP) [7]. 6-Phosphogluconate dehydrogenase (6-PGDH), a key enzyme in the oxidative PPP, is aberrantly activated and plays an important ro

FAQs

What role does 6-PGDH play in the study of gastric cancer therapy?

6-PGDH is investigated as a therapeutic target because it catalyzes a key step in the oxidative pentose phosphate pathway and is reported to be aberrantly elevated in gastric cancer.

How does inhibiting or knocking down 6-PGDH affect gastric cancer cells?

6-PGDH knockdown reduces 6-PGDH levels and activity, decreases growth, and increases cell sensitivity to 5-fluorouracil.

Which mechanisms connect 6-PGDH inhibition to apoptosis in gastric cancer?

The study links 6-PGDH inhibition to disrupted lipid biosynthesis and redox homeostasis, with oxidative stress and AMPK activation contributing to growth arrest and apoptosis, supported by in vitro and in vivo validation.

Sep 24, 2026

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