Suppression of lung adenocarcinoma migration through organelle alkalization by human lactoferrin – albumin fusion

Abstract

The fusion of human serum albumin with human lactoferrin (hLF-HSA) exerts strong anti-migratory effects in human lung adenocarcinoma cells through matrix metalloproteinase 1 (MMP1) downregulation. We demonstrate that hLF-HSA disrupts organelle pH homeostasis via Na+/H+ exchanger 7 (NHE7) upregulation, inducing organelle alkalization in the Golgi apparatus. This organelle dysfunction alters the Golgi-mediated secretome, leading to MMP1 downregulation and suppression of cell migration. hLF-HSA-induced MMP1 downregulation also reverses epithelial-mesenchymal transition (EMT), further suppressing migration. Additionally, hLF-HSA-driven activation of caveolae-mediated endocytosis (CavME) signaling downregulated MMP1 expression without NHE7 upregulation. These findings highlight that hLF-HSA–mediated disruption of organelle pH regulation and CavME activation represents a potential strategy to suppress cancer cell migration. Impact statement This work reveals a previously unrecognized link between organelle pH dysregulation and cancer cell migration. By identifying hLF-HSA as a dual modulator of Golgi function and endocytic signaling, it provides a mechanistic basis for developing novel anti-metastatic strategies targeting intracellular trafficking rather than cytotoxicity.