Muñoz-Uribe Matías, Martin-Martin Antonia, Burgos Rafael A, Alarcón Pablo, López-Contreras Freddy, Cordero José, Barrera Nelson P, Chipon Carina, López-Muñoz Rodrigo
Facultad de Ciencias Veterinarias, Instituto de Farmacología y Morfofisiología, Universidad Austral de Chile, Valdivia, Chile.
Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
Metabolomics. 2025 Jun 14;21(4):82. doi: 10.1007/s11306-025-02278-4.
Polyamines (putrescine, spermidine, and spermine) are essential molecules for DNA stability and tumor cell proliferation, including in non-small cell lung cancer (NSCLC). AMD1 (S-adenosylmethionine decarboxylase), a critical enzyme in polyamine metabolism, decarboxylates S-adenosylmethionine, a central methyl group donor. SAM486A, an AMD1 inhibitor, has demonstrated therapeutic potential in hematologic and solid tumors.
This study evaluates the effects of SAM486A on NSCLC cell lines A549 and H1299, focusing on polyamine metabolism, DNA methylation, cell proliferation, migration, and eIF5A hypusination.
Untargeted GC-MS metabolomics, followed by Ingenuity Pathway Analysis (IPA), was conducted to evaluate the broad metabolic impact of SAM486A. Further characterizations were performed using Western blotting, cell viability, ELISA, and migration assays in A549 and H1299 cells treated with SAM486A. Transcriptomic and survival analyses from the TCGA-LUAD cohort were also integrated to assess clinical relevance.
SAM486A reduced proliferation and migration in both NSCLC cell lines, with A549 displaying greater sensitivity. Metabolomic profiling revealed distinct responses: A549 accumulated L-methionine and showed reduced cysteine and spermidine, while H1299 exhibited increased cysteine and preserved spermidine levels. IPA predicted a shift toward DNA methylation in A549, which was experimentally confirmed by increased 5-methyl-2'-deoxycytidine levels. eIF5A hypusination remained unchanged in both lines. Spermidine rescue experiments showed functional recovery in H1299, but not A549, supporting differential polyamine uptake. Transcriptomic and survival analyses in LUAD patients mirrored these findings, linking low AMD1 expression to favorable outcomes.
These findings suggest that AMD1 inhibition by SAM486A induces a metabolic and epigenetic phenotype resembling that of LUAD tumors with favorable prognosis, supporting its potential as a targeted therapeutic strategy in NSCLC subsets with low AMD1 expression.
多胺（腐胺、亚精胺和精胺）是DNA稳定性和肿瘤细胞增殖所必需的分子，包括在非小细胞肺癌（NSCLC）中。AMD1（S-腺苷甲硫氨酸脱羧酶）是多胺代谢中的一种关键酶，可使S-腺苷甲硫氨酸（一种重要的甲基供体）脱羧。SAM486A是一种AMD1抑制剂，已在血液系统肿瘤和实体瘤中显示出治疗潜力。
本研究评估SAM486A对NSCLC细胞系A549和H1299的影响，重点关注多胺代谢、DNA甲基化、细胞增殖、迁移和eIF5A的hypusination修饰。
进行非靶向气相色谱-质谱代谢组学分析，随后进行Ingenuity通路分析（IPA），以评估SAM486A对广泛代谢的影响。使用蛋白质免疫印迹法、细胞活力检测、酶联免疫吸附测定（ELISA）以及对用SAM486A处理的A549和H1299细胞进行迁移实验，进行进一步的表征。还整合了来自TCGA-LUAD队列的转录组学和生存分析，以评估临床相关性。
SAM486A降低了两种NSCLC细胞系的增殖和迁移能力，其中A549表现出更高的敏感性。代谢组学分析揭示了不同的反应：A549积累L-甲硫氨酸，半胱氨酸和亚精胺水平降低，而H1299的半胱氨酸增加，亚精胺水平保持不变。IPA预测A549向DNA甲基化转变，这通过5-甲基-2'-脱氧胞苷水平的升高在实验中得到证实。两种细胞系中eIF5A的hypusination修饰均保持不变。亚精胺挽救实验表明H1299功能恢复，但A549没有，这支持了多胺摄取的差异。LUAD患者的转录组学和生存分析反映了这些发现，将低AMD1表达与良好预后联系起来。
这些发现表明，SAM486A抑制AMD1会诱导一种代谢和表观遗传表型，类似于预后良好的LUAD肿瘤，支持其作为低AMD1表达的NSCLC亚组靶向治疗策略的潜力。
