Prodigiosin inhibits Transforming growth factor β signaling by interfering receptor recycling and subcellular translocation in epithelial cells.

Prodigiosin (PG), a naturally occurring polypyrrole red pigment produced by numerous microorganisms including some Serratia and Streptomyces strains. PG has exhibited promising anticancer activity; however, the molecular mechanisms of action of PG on malignant cells remain ambiguous. Transforming growth factor β (TGF-β) is a multifunctional cytokine governs a wide array of cellular processes in development and tissue homeostasis. Malfunctions of the TGF-β signaling are associated with numerous human cancers. Emerging evidence underscores the significance of internalized TGF-β receptors and their intracellular trafficking in initiating signaling cascades. In this study, we identified PG as a potent inhibitor of the TGF-β pathway. PG blocked TGF-β signaling by targeting multiple sites of this pathway, including facilitates the sequestering of TGF-β receptors in the cytoplasm by impeding the recycling of type II TGF-β receptors to the cell surface. Additionally, PG prompts a reduction in the abundance of receptors on the cell surface through the disruption of receptor glycosylation. In lung cancer A549 and HepG2 cells, nanomolar concentrations of PG substantially diminish TGF-β-triggered phosphorylation of Smad2 protein. This attenuation is further reflected in the suppression of downstream target gene expression, including those encoding fibronectin, plasminogen activator inhibitor-1 (PAI-1), and N-cadherin. Significance Statement Prodigiosin (PG) emerges as a potent TGF-β pathway inhibitor, disrupting receptor trafficking and glycosylation, reduces TGF-β signaling and downstream gene expression. These findings not only shed light on PG's potential therapeutic role but also present a captivating avenue for future anti-TGF-β strategies.