NRF2-活化的肺癌细胞系的二甲双胍限制性运动涉及NAD+缺失，而不是AMPK-或BACH1信号传导
Metformin-restricted motility of an NRF2-activated lung cancer cell line involves NAD+ depletion, rather than AMPK- or BACH1 signaling.
摘要(中文译文)
NRF2是一种氧化还原敏感的细胞保护性转录因子。癌细胞利用NRF2抑制因子KEAP1的突变以及随之而来的NRF2过度激活，从而增强治疗耐药性和恶性程度。AMP活化蛋白激酶（AMPK）可导致NRF2磷酸化，并在KEAP1缺陷背景下增强βTrCP介导的降解。本研究探讨了二甲双胍对AMPK的药理激活是否降低KEAP1缺陷型A549肺腺癌细胞中NRF2的水平及应激耐受性。二甲双胍处理未改变NRF2半衰期、所选经典NRF2靶基因的表达，或对顺铂或紫杉醇的敏感性。相反，二甲双胍降低了BACH1的丰度，BACH1是一种不仅与NRF2竞争而且促进癌细胞迁移的转录因子。在A549细胞中检测潜在的AMPK-BACH1运动轴时，我们观察到二甲双胍处理后划痕愈合和Transwell实验中细胞迁移减少。然而，BACH1的敲低或过表达，或AMPK敲低，均否定了二甲双胍主要通过BACH1或AMPK损害细胞迁移的结论。二甲双胍作为线粒体复合物I抑制剂，增加了细胞NADH/NAD+比值。补充烟酰胺单核苷酸以促进NAD+合成可恢复二甲双胍处理细胞的运动能力。因此，二甲双胍给药似乎并未减轻NRF2活性，而是抑制了KEAP1缺陷型A549细胞的迁移。后者与NAD+耗竭相关，而非AMPK激活或BACH1下调。
Abstract
NRF2 is a redox-sensitive and cytoprotective transcription factor. Cancer cells exploit mutations in the NRF2-inhibitor KEAP1 and subsequent NRF2 overactivation for increased therapy resistance and malignancy. AMP-activated protein kinase (AMPK) leads to NRF2 phosphorylation and enhanced βTrCP-mediated degradation in KEAP1-deficient contexts. This study examined whether pharmacological activation of AMPK by metformin decreased levels of NRF2 and stress resilience in KEAP1-deficient A549 lung adenocarcinoma cells. Metformin treatment did not alter NRF2 half-life, expression of selected canonical NRF2 target genes, or sensitivity to cisplatin or taxol. Instead, metformin reduced abundance of BACH1, a transcription factor not only competing with NRF2 but also favoring migration of cancer cells. Testing for a potential AMPK-BACH1 motility axis in A549 cells, we observed reduced cell migration in wound closure and transwell assays upon treatment with metformin. However, depletion or overexpression of BACH1, or AMPK knockdown negated that metformin impaired cell migration primarily via BACH1 or AMPK. Metformin, as mitochondrial complex I inhibitor, increased the cellular NADH/NAD+ ratio. Supplementation with nicotinamide mononucleotide fueling NAD+ synthesis restored motility in metformin-treated cells. Thus, metformin administration does not seem to alleviate NRF2 activity but suppresses migration in KEAP1-deficient A549 cells. The latter is linked to NAD+ depletion, rather than AMPK activation or BACH1 downregulation.
如何引用
AMA
Shara Natalia Sosa Cabrera, Sophie Huber, Barbara Braunböck-Müller, Elke H Heiss. Metformin-restricted motility of an NRF2-activated lung cancer cell line involves NAD+ depletion, rather than AMPK- or BACH1 signaling.. Scientific reports. 2026; doi:10.1038/s41598-026-61444-3.
APA
Shara Natalia Sosa Cabrera, Sophie Huber, Barbara Braunböck-Müller, Elke H Heiss (2026). Metformin-restricted motility of an NRF2-activated lung cancer cell line involves NAD+ depletion, rather than AMPK- or BACH1 signaling.. Scientific reports. https://doi.org/10.1038/s41598-026-61444-3
GB/T 7714
Shara Natalia Sosa Cabrera, Sophie Huber, Barbara Braunböck-Müller, Elke H Heiss. Metformin-restricted motility of an NRF2-activated lung cancer cell line involves NAD+ depletion, rather than AMPK- or BACH1 signaling.[J]. Scientific reports, 2026 doi:10.1038/s41598-026-61444-3.
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