Gramicidin Inhibits Lung Cancer Metastasis by Suppressing the ABL‐MMP9 Signaling Axis

ABSTRACT

Lung cancer, the deadliest malignant tumor worldwide, consists predominantly of non‐small cell lung cancer (NSCLC) and accounts for most cancer‐related deaths; its aggressive metastatic nature severely compromises treatment outcomes and overall survival. Abelson tyrosine kinase (ABL), a key regulator of metastasis across multiple tumor types, has emerged as a promising therapeutic target. Gramicidin's effects on NSCLC cell proliferation, migration, and invasion were assessed using CCK‐8, colony formation, Transwell, and wound healing assays. ABL protein levels were analyzed using Western blot (WB). The effects of ABL expression on MMP9 levels and cellular migration and invasion were examined in ABL‐knockdown cells using gelatin zymography, WB, Transwell, and wound healing assays. ABL‐overexpressing cells were treated with gramicidin to examine gramicidin's suppression of the ABL‐MMP9 axis using WB, Transwell, and wound healing assays. In a BALB/c nude mouse model of lung metastasis established via tail vein injection of tumor cells, we evaluated the inhibitory effects of gramicidin on metastatic nodule formation in vivo and its influence on ABL and MMP9 expressions. Gramicidin significantly suppressed lung cancer cell proliferation, migration, and invasion. ABL was upregulated in human lung cancer cells and could be effectively suppressed by gramicidin treatment. Gramicidin downregulated MMP9 expression by suppressing ABL protein expression, thereby attenuating lung cancer metastasis. In vivo , gramicidin treatment reduced the number of lung metastatic nodules and simultaneously downregulated ABL and MMP9 proteins in lung tissue, effects that were partially reversed by ABL overexpression. This study revealed the molecular mechanism by which gramicidin inhibits lung cancer metastasis through suppression of the ABL‐MMP9 axis, providing a theoretical foundation for developing gramicidin‐based anti‐metastatic strategies.