Prodigiosin Inhibits Transforming Growth Factor β Signaling by Interfering Receptor Recycling and Subcellular Translocation in Epithelial Cells.

Prodigiosin (PG) is 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 that governs a wide array of cellular processes in development and tissue homeostasis. Malfunctions of 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 facilitating 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 the receptor glycosylation. In human Caucasian lung carcinoma cells and human hepatocellular cancer cell line 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, and N-cadherin. SIGNIFICANCE STATEMENT: Prodigiosin (PG) emerges from this study as a potent TGF-β pathway inhibitor, disrupting receptor trafficking and glycosylation and reducing 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 towards future anti-TGF-β strategies.