Nortriptyline Inhibits Lysosomal Exocytosis-Mediated SASP During Gastric Cancer Progression via Targeting HOXA1-PITX2 Phase Separation.

ABSTRACT: Lysosomal exocytosis, a calcium-dependent secretory process, facilitates extracellular release of cargos that promote cancer progression, though its regulatory pathways and therapeutic strategies are poorly understood. Herein, using combined transcriptomic and proteomic approaches, we identify homeobox A1 (HOXA1) as a functional partner of paired like homeodomain 2 (PITX2) within biomolecular condensates forming via liquid-liquid phase separation. Mechanistically, HOXA1-PITX2 complex facilitates the expression of mucolipin 1 (MCOLN1) and RAS-related protein Rab-3A (RAB3A), which drive lysosomal exocytosis of galectin-1 (LGALS1) and insulin like growth factor binding protein 7 (IGFBP7) from senescent gastric cancer cells. This process potentiates AKT activation and epithelial-mesenchymal tr

SUBMITTER: Zhou Y 

PROVIDER: S-EPMC12697896 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature