GKB202 suppresses endothelin-1/ERK signaling in pancreatic cancer cells: Potential implications for circulating tumor cell regulation

Circulating tumor cells (CTCs) play a key role in cancer metastasis. However, the complex tumor microenvironment means that targeting these cells therapeutically remains a major clinical challenge. The natural compound GKB202, derived from the mycelium of Antrodia cinnamomea, has been shown to possess anti-cancer properties. Yet, its role in regulating signaling mechanisms preceding cancer metastasis remains unclear. In this study, RNA-seq analysis demonstrated that GKB202 treatment reduced endothelin-1 (ET-1) expression and downregulated signaling cascades in CTCs derived from pancreatic cancer patients. Furthermore, conditioned medium assays indicated that GKB202 prevented cancer cells from stimulating endothelial cells to produce ET-1 and activate ERK/p-ERK downstream signaling, suggesting its potential to inhibit CTCs and prevent the extravasation process. Using protein interaction prediction tools and pathway analysis (STRING and KEGG), we identified interactions between ET-1, MAPK, and AKT, which are associated with tumor angiogenesis pathways. Molecular docking analysis further revealed that GKB202 can act as an ET_B receptor antagonist, with a binding energy comparable to that of Bosentan, a known ET_B receptor blocker. In addition, combination index (CI) analysis demonstrated that GKB202 exhibited significant synergistic effects with 5-fluorouracil (5-FU), a first-line chemotherapeutic agent. Based on these findings, this study highlights the potential of GKB202 to inhibit cancer cell-induced ET-1 production in endothelial cells, providing novel insights into the tumor microenvironment. Furthermore, as a naturally derived small-molecule compound, GKB202 may serve as a promising candidate for future therapeutic interventions.