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ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Pharmacology of Anti-Cancer Drugs
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1540567
This article is part of the Research Topic The Role of Tumor Microenvironment in Malignant Progression and Target Validation View all 5 articles
Fenvalerate exposure induces AKT/AMPK-dependent alterations in glucose metabolism in hepatoma cells
Provisionally accepted
Lu Sun 1
Zheng-Guo Cui 2
Qianwen Feng 3*
Jibran Sualeh Muhammad 4
Yu-Jie Jin 5
Songji Zhao 6 Lingqi Zhou 1*
Chengai Wu 7,8*- 1 Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong Province, China
- 2 Department of Environmental Health, Faculty of Medical Sciences, University of Fukui, Fukui, Fukui, Japan
- 3 Biocytogen Phaceuticals,, Beijing, China
- 4 University of Birmingham, Birmingham, England, United Kingdom
- 5 The First hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
- 6 Fukushima Global Medical Science Center, Fukushima Medical University, Fukushima, Fukushima, Japan
- 7 Institute for Trauma Recovery, Department of Anesthesiology, University of North Carolina, Chapel Hill, North Carolina, United States
- 8 Institute of Orthopaedic Trauma, Beijing, China
Fenvalerate (Fen) is a synthetic pyrethroid insecticide significantly associated with an increased risk of type 2 diabetes. Tumor cells exhibit a shift in glucose metabolism, known as the Warburg effect. Accordingly, we aimed to elucidate whether Fen interferes with insulin signaling and affects hepatoma cell metabolism. Our results demonstrated that Fen promotes glucose uptake, lactate production, and ATP generation in various cancer cells. Moreover, Fen enhanced insulin receptor phosphorylation and upregulated p-AKT/p-AMPK expression. Fen enhanced insulin receptor sensitivity and endocytosis via reactive oxygen species generation rather than the PP2B pathway. Additionally, the antioxidants N-acetyl-L-cysteine and ascorbic acid reversed the Feninduced increase in glycolysis. Finally, chronic Fen exposure protected hepatoma cells against metformin-induced cell death via the AKT/AMPK pathway. These findings raise concerns regarding the safety of Fen and its potential role in altering cancer cell metabolism, affecting insulin signaling and treating drug resistance, thereby necessitating further research.
Keywords: Fenvalerate, Warburg-like effect, Cancer cell metabolism, Reactive oxygen species generation, Insulin receptor
Received: 06 Dec 2024; Accepted: 27 Jan 2025.
Copyright: © 2025 Sun, Cui, Feng, Muhammad, Jin, Zhao, Zhou and Wu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Qianwen Feng, Biocytogen Phaceuticals,, Beijing, China
Lingqi Zhou, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, 510623, Guangdong Province, China
Chengai Wu, Institute for Trauma Recovery, Department of Anesthesiology, University of North Carolina, Chapel Hill, North Carolina, United States
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