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  3. High glucose enhances the aggressiveness of lung adenocarcinoma via activating epidermal growth factor receptor/signal transducer and activator of transcription 3 pathways

High glucose enhances the aggressiveness of lung adenocarcinoma via activating epidermal growth factor receptor/signal transducer and activator of transcription 3 pathways

  • J Nutr Biochem. 2023 Jun 2;109399. doi: 10.1016/j.jnutbio.2023.109399.
Supannika Sorin 1,  Yubin Zhou 2,  Kanyarat Thithuan 1,  Kullanat Khawkhiaw 1,  Fuchun Zeng 2,  Tummarat Ruangpratyakul 3,  Surang Chomphoo 4,  Wunchana Seubwai 5,  Sopit Wongkham 1,  Charupong Saengboonmee 6
Affiliations

Affiliations

  • 1 Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
  • 2 Department of Thoracic Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China.; Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, Sichuan 610072, China.
  • 3 Department of Surgery, Roi Et Hospital, Muaeng Roi Et, Roi Et 45000, Thailand.
  • 4 Department of Anatomy, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
  • 5 Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Department of Forensic Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
  • 6 Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand. Electronic address: [email protected].
PMID: 37271322 DOI: 10.1016/j.jnutbio.2023.109399
Abstract

Epidemiological studies revealed hyperglycemia as a poor prognostic factor for lung adenocarcinoma with unclear molecular mechanisms. The present study thus aimed to investigate the effects of high glucose on the progression of lung adenocarcinoma and its underlying mechanisms. Lung adenocarcinoma cell lines, A549 and RERF-LC-KJ, were cultured in 5.6 mM glucose (normal glucose; NG) or 25 mM glucose (high glucose; HG) resembling euglycemia and hyperglycemia. Cells were examined for proliferation by the MTT assay, and migration-invasion using Transwell. The expressions of signaling proteins in epidermal growth factor receptor (EGFR) pathways and their downstream targets were investigated using Western blots. The effects of diabetes mellitus (DM) and hyperglycemia on lung adenocarcinoma growth in vivo were studied in streptozotocin-induced diabetic BALB/cAJcl-Nu/Nu mice and their non-diabetic counterparts. High glucose significantly promoted proliferation, migration, and invasion of lung adenocarcinoma cells compared with those in normal glucose (P<0.05). Western blot analyses showed the increased ratio of pEGFR/EGFR in cells cultured in high glucose and subsequently activated the signal transducer and activator of transcription 3 (STAT3). Epithelial-mesenchymal (EMT) markers were also altered in lung adenocarcinoma cells in high glucose conditions, corresponding with increased migration and invasion abilities. Erlotinib, an EGFR inhibitor, significantly reversed high glucose-induced aggressive phenotypes confirming high glucose-enhancing lung adenocarcinoma progression via the activation of EGFR. DM and hyperglycemia also promoted the growth of lung adenocarcinoma xenografts in vivo in which erlotinib significantly suppressed the growth of tumors (P<0.05) suggesting EGFR inhibitor as an effective therapeutic agent for lung adenocarcinoma with DM.

Keywords

Cancer Progression; Diabetes mellitus; Epidermal Growth Factor Receptor; Hyperglycemia; Lung Cancer.

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