Anti-Proliferation and Anti-Fibrotic Effects of Fucoidan on Leiomyoma Cells

Abstract

Uterine leiomyomas (ULs) are benign uterine tumors, and the most typically pathophysiologic feature of ULs is excessive extracellular matrix (ECM) production. Fucoidan is a polysaccharide extracted from brown seaweeds shows potent anti-tumor and anti-fibrotic properties in various tumors. However, the effect of fucoidanon on ULs cells remains unclear. Recently, we found that using a dose of 0.5 mg/ml fucoidan caused a 50% growth inhibition of ELT-3 (Eker rat leiomyoma tumor-derived cells) and decreased the stem cell activity after 48 h. Besides, we also found that fucoidan induced sub-G1 cell cycle arrest and apoptosis, as well as reduced its related protein expression, such as cyclin D1, Bax, and Bcl-2. To simulate the generated state of uterine leiomyoma, we used transforming growth factor beta (TGF-β) to stimulate ELT-3 cell growth, and found that fucoidan down-regulated fibronectin, vimentin, alpha-smooth muscle actin (α-SMA) and the COL1A1 protein levels in TGFβ3-induced ELT-3 cells. In the cellular mechanism, we found that fucoidan abrogated TGFβ3-induced levels of p-Smad2 and phospho-extracellular signal-regulated kinase 1/2 (p-ERK1/2), as well as β-catenin translocation into the nucleus. In addition, we also conducted in vivo experiments to confirm the inhibitory effects of fucoidan in nude mouse xenograft models. We found that fucoidan not only suppressed xenograft tumor growth, but also decreased the proportion of proliferating cell nuclear antigen (PCNA, growth-promoting marker), fibronectin (ECM marker)-, and α-SMA (myofibroblast marker)-positive cells in tumor tissue. Taken together, our results indicated that fucoidan displays anti-proliferation and anti-fibrotic effects and exerts protective effects against ULs development in vitro and in vivo.