Eltrombopag binds SDC4 directly and enhances MAPK signaling and macropinocytosis in cancer cells.

ABSTRACT: Syndecan-4 (SDC4) is a single-pass transmembrane glycoprotein implicated in a variety of oncogenic signaling pathways. It is also an intrinsically disordered protein and considered "undruggable". In the present study, we confirmed that knocking out SDC4 in pancreatic cancer cells markedly impaired macropinocytosis, colony formation, as well as xenograft tumor initiation and growth. Quantitative proteomic profiling of Sdc4 knockout (KO) cells revealed significant changes in cell metabolic pathways. In a cellular protein-based ligand interaction screening, we identified that Eltrombopag (ETBP), an FDA-approved agonist of the thrombopoietin receptor (TPOR) for immune thrombocytopenia, could directly bind to SDC4 with a Kd value of ~2 µM. We showed that the transmembrane motif was essential fo

SUBMITTER: Cui C 

PROVIDER: S-EPMC9251693 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature