Sun Lu, Cui Zheng-Guo, Feng Qianwen, Muhammad Jibran Sualeh, Jin Yu-Jie, Zhao Songji, Zhou Lingqi, Wu Cheng-Ai
Department of Pediatric Cardiology, Heart Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
Department of Environmental Health, University of Fukui School of Medical Sciences, Fukui, Japan.
Front Pharmacol. 2025 Feb 25;16:1540567. doi: 10.3389/fphar.2025.1540567. eCollection 2025.
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.
The cells were subjected to Fen to assess glucose uptake, acidification, oxygen consumption, and ATP production. ROS generation, mitochondrial membrane potentials, and protein expression were evaluated by flow cytometry, immunofluorescence microscopy, and western blot analyses.
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 Fen-induced 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.
氰戊菊酯（Fen）是一种合成拟除虫菊酯类杀虫剂，与2型糖尿病风险增加显著相关。肿瘤细胞表现出葡萄糖代谢的改变，即所谓的瓦伯格效应。因此，我们旨在阐明氰戊菊酯是否会干扰胰岛素信号传导并影响肝癌细胞代谢。
用氰戊菊酯处理细胞，以评估葡萄糖摄取、酸化、耗氧量和ATP生成。通过流式细胞术、免疫荧光显微镜和蛋白质印迹分析评估活性氧生成、线粒体膜电位和蛋白质表达。
我们的结果表明，氰戊菊酯可促进多种癌细胞的葡萄糖摄取、乳酸生成和ATP生成。此外，氰戊菊酯增强胰岛素受体磷酸化并上调p-AKT/p-AMPK表达。氰戊菊酯通过产生活性氧而非PP2B途径增强胰岛素受体敏感性和内吞作用。此外，抗氧化剂N-乙酰半胱氨酸和抗坏血酸可逆转氰戊菊酯诱导的糖酵解增加。最后，长期暴露于氰戊菊酯可通过AKT/AMPK途径保护肝癌细胞免受二甲双胍诱导的细胞死亡。
这些发现引发了对氰戊菊酯安全性及其在改变癌细胞代谢、影响胰岛素信号传导和治疗耐药性方面潜在作用的关注，因此有必要进一步研究。
