Surgery · 2026
Lactate-associated pyruvate kinase muscle isoform 2 nuclear enrichment and ferroptotic stress responses in lung cancer.
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Li Lixiu, Zhong Aihong, Huang Mingxiang, Lin Yujun, Chen Wenxin, Ni Zhijie, Chen Shuxing, He Feng, Huang Renjie
Аннотация
BACKGROUND: Ferroptosis is an iron-dependent form of regulated cell death with therapeutic potential in cancer. However, metabolic alterations within the tumor microenvironment may influence the sensitivity of lung cancer cells to ferroptotic stress. This study investigated the association between lactate exposure, pyruvate kinase muscle isoform 2 signaling, and cellular responses to RSL3-induced ferroptotic stress.
METHODS: Human H1299 lung cancer cells were treated with lactate (20 mmol/L; 24 hours), RSL3 (2 μmol/L), and the pyruvate kinase muscle isoform 2-targeting compound shikonin (1 μmol/L). Pyruvate kinase muscle isoform 2 expression and subcellular localization were assessed by immunofluorescence, and pyruvate kinase muscle isoform 2 immunoreactivity was evaluated by immunohistochemistry. Patient-derived lung cancer organoids were used to assess 3-dimensional growth. Wound-healing and Transwell assays were performed to evaluate wound closure and Transwell cell counts, respectively. SLC7A11 and glutathione peroxidase 4 protein levels were examined by Western blotting.
RESULTS: Under RSL3-induced ferroptotic stress, lactate treatment was associated with increased pyruvate kinase muscle isoform 2 nuclear enrichment and immunoreactivity, whereas shikonin partially attenuated these changes. Lactate partially alleviated RSL3-induced growth inhibition in patient-derived lung cancer organoids and increased wound closure and Transwell cell counts relative to RSL3 treatment alone. These lactate-associated phenotypic changes were partially attenuated by shikonin. RSL3 reduced SLC7A11 and glutathione peroxidase 4 protein levels, whereas lactate cotreatment increased the levels of both proteins. Shikonin attenuated the lactate-associated increase in glutathione peroxidase 4, while its effect on SLC7A11 was less pronounced.
CONCLUSION: Lactate treatment was associated with increased pyruvate kinase muscle isoform 2 nuclear enrichment, higher SLC7A11 and glutathione peroxidase 4 protein levels, and partial attenuation of RSL3-induced growth inhibition. These findings suggest that lactate-associated pyruvate kinase muscle isoform 2 signaling may contribute to reduced sensitivity to ferroptotic stress in lung cancer. Further genetic and mechanistic studies are required to establish the causal role of pyruvate kinase muscle isoform 2 and determine whether nuclear pyruvate kinase muscle isoform 2 directly regulates SLC7A11 and glutathione peroxidase 4 expression.
METHODS: Human H1299 lung cancer cells were treated with lactate (20 mmol/L; 24 hours), RSL3 (2 μmol/L), and the pyruvate kinase muscle isoform 2-targeting compound shikonin (1 μmol/L). Pyruvate kinase muscle isoform 2 expression and subcellular localization were assessed by immunofluorescence, and pyruvate kinase muscle isoform 2 immunoreactivity was evaluated by immunohistochemistry. Patient-derived lung cancer organoids were used to assess 3-dimensional growth. Wound-healing and Transwell assays were performed to evaluate wound closure and Transwell cell counts, respectively. SLC7A11 and glutathione peroxidase 4 protein levels were examined by Western blotting.
RESULTS: Under RSL3-induced ferroptotic stress, lactate treatment was associated with increased pyruvate kinase muscle isoform 2 nuclear enrichment and immunoreactivity, whereas shikonin partially attenuated these changes. Lactate partially alleviated RSL3-induced growth inhibition in patient-derived lung cancer organoids and increased wound closure and Transwell cell counts relative to RSL3 treatment alone. These lactate-associated phenotypic changes were partially attenuated by shikonin. RSL3 reduced SLC7A11 and glutathione peroxidase 4 protein levels, whereas lactate cotreatment increased the levels of both proteins. Shikonin attenuated the lactate-associated increase in glutathione peroxidase 4, while its effect on SLC7A11 was less pronounced.
CONCLUSION: Lactate treatment was associated with increased pyruvate kinase muscle isoform 2 nuclear enrichment, higher SLC7A11 and glutathione peroxidase 4 protein levels, and partial attenuation of RSL3-induced growth inhibition. These findings suggest that lactate-associated pyruvate kinase muscle isoform 2 signaling may contribute to reduced sensitivity to ferroptotic stress in lung cancer. Further genetic and mechanistic studies are required to establish the causal role of pyruvate kinase muscle isoform 2 and determine whether nuclear pyruvate kinase muscle isoform 2 directly regulates SLC7A11 and glutathione peroxidase 4 expression.