SAM486A-induced inhibition of AMD1: metabolic and epigenetic implications in non-small cell lung cancer cells.

INTRODUCTION

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.

OBJECTIVES

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.