Phlorotannins from Ecklonia cava Regulate Dual Signaling Pathways, IL-17RA/Act1 and ERK1/2, to Suppress Ovarian Cancer Progression and Tumor-Associated Macrophage Activation.

BACKGROUND: Marine-derived secondary metabolites such as phlorotannins from the edible brown alga Ecklonia cava exhibit diverse bioactivities. However, their mechanisms in inflammation-associated cancer remain insufficiently understood.

METHODS: This study explored the anticancer potential of three major phlorotannins (dieckol, 7-phloroeckol, and 8,8'-bieckol) through network pharmacology, molecular docking, molecular dynamics simulations, and in vitro validation in SKOV3 ovarian cancer cells and tumor-associated macrophages (TAMs).

RESULTS: Computational analyses revealed stable binding of phlorotannins to IL-17RA, with 7-phloroeckol and 8,8'-bieckol preferentially engaging loop-proximal regions of the receptor, while dieckol interacted with spatially distinct residues. In SKOV3 ovarian cancer cells, phlorotannins suppressed migration and invasion by approximately 40 to 60%, accompanied by reduced MMP expression linked to IL-17RA-Act1 signaling attenuation and by increased TIMP1 expression in association with transient ERK1/2 activation. In TAMs, phlorotannins attenuated pro-tumorigenic cytokine production and polarization marker expression, indicating suppression of tumor-supportive immune activity.

CONCLUSIONS: Collectively, these findings demonstrate that E. cava-derived phlorotannins exert anti-metastatic effects through dual regulation of IL-17RA/Act1 and ERK1/2 signaling pathways, offering mechanistic insight into their therapeutic potential against inflammation-driven malignancies.