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  3. 6-Phosphogluconate dehydrogenase promotes glycolysis and fatty acid synthesis by inhibiting the AMPK pathway in lung adenocarcinoma cells

6-Phosphogluconate dehydrogenase promotes glycolysis and fatty acid synthesis by inhibiting the AMPK pathway in lung adenocarcinoma cells

  • Cancer Lett. 2024 Oct 1:601:217177. doi: 10.1016/j.canlet.2024.217177.
Jun Wu 1,  Yong Chen 2,  Hui Zou 3,  Kaiyue Xu 4,  Jiaqi Hou 5,  Mengmeng Wang 5,  Shuyu Tian 5,  Mingjun Gao 5,  Qinglin Ren 5,  Chao Sun 6,  Shichun Lu 6,  Qiang Wang 7,  Yusheng Shu 8,  Shouyu Wang 9,  Xiaolin Wang 10
Affiliations

Affiliations

  • 1 Medical College, Yangzhou University, Yangzhou, China; Department of Thoracic Surgery, Northern Jiangsu People's Hospital, Yangzhou, China; Yangzhou Key Laboratory of Thoracic and Cardiac Surgery, Yangzhou, China.
  • 2 Department of Thoracic Surgery, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
  • 3 The Yangzhou School of Clinical Medicine of Nanjing Medical University, Yangzhou, China; Department of Thoracic Surgery, Northern Jiangsu People's Hospital, Yangzhou, China.
  • 4 Department of Radiation Oncology, Suzhou Municipal Hospital, Suzhou, China.
  • 5 First College of Clinical Medicine, Dalian Medical University, Dalian, China.
  • 6 Department of Thoracic Surgery, Northern Jiangsu People's Hospital, Yangzhou, China.
  • 7 Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Anhui Provincial Innovation Institute for Pharmaceutical Basic Research, Innovative Institute of Tumor Immunity and Medicine (ITIM), Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei, China.
  • 8 The Yangzhou School of Clinical Medicine of Nanjing Medical University, Yangzhou, China; Department of Thoracic Surgery, Northern Jiangsu People's Hospital, Yangzhou, China; Yangzhou Key Laboratory of Thoracic and Cardiac Surgery, Yangzhou, China. Electronic address: 18051061999@yzu.edu.cn.
  • 9 Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Anhui Provincial Innovation Institute for Pharmaceutical Basic Research, Innovative Institute of Tumor Immunity and Medicine (ITIM), Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei, China. Electronic address: shouyuwang@ahmu.edu.cn.
  • 10 Medical College, Yangzhou University, Yangzhou, China; Department of Thoracic Surgery, Northern Jiangsu People's Hospital, Yangzhou, China; Yangzhou Key Laboratory of Thoracic and Cardiac Surgery, Yangzhou, China. Electronic address: 18051063909@yzu.edu.cn.
PMID: 39179096 DOI: 10.1016/j.canlet.2024.217177
Abstract

Abnormal metabolism has emerged as a prominent hallmark of Cancer and plays a pivotal role in carcinogenesis and progression of lung adenocarcinoma (LUAD). In this study, single-cell Sequencing revealed that the metabolic Enzyme 6-phosphogluconate dehydrogenase (PGD), which is a critical regulator of the pentose phosphate pathway (PPP), is significantly upregulated in the malignant epithelial cell subpopulation during malignant progression. However, the precise functional significance of PGD in LUAD and its underlying mechanisms remain elusive. Through the integration of TCGA database analysis and LUAD tissue microarray data, it was found that PGD expression was significantly upregulated in LUAD and closely correlated with a poor prognosis in LUAD patients. Moreover, in vitro and in vivo analyses demonstrated that PGD knockout and inhibition of its activity mitigated the proliferation, migration, and invasion of LUAD cells. Mechanistically, immunoprecipitation-mass spectrometry (IP-MS) revealed for the first time that IQGAP1 is a robust novel interacting protein of PGD. PGD decreased p-AMPK levels by competitively interacting with the IQ domain of the known AMPKα binding partner IQGAP1, which promoted glycolysis and fatty acid synthesis in LUAD cells. Furthermore, we demonstrated that the combination of Physcion (a PGD-specific inhibitor) and metformin (an AMPK agonist) could inhibit tumor growth more effectively both in vivo and in vitro. Collectively, these findings suggest that PGD is a potential prognostic biomarker and therapeutic target for LUAD.

Keywords

6-Phosphogluconate dehydrogenase; AMPK pathway; Lung adenocarcinoma; Pentose phosphate pathway; Single-cell sequencing.

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