Fucoidan induces changes in the epithelial to mesenchymal transition and decreases metastasis by enhancing ubiquitin-dependent TGF  receptor degradation in breast cancer

Abstract

Fucoidan, a polysaccharide extracted from brown seaweeds, reduces tumor cell proliferation. Fucoidan inhibits the growth of breast cancer cells such as 4T1 and MDA-MB-231 and decreases their cell colony formation. Moreover, fucoidan reduces metastatic lung nodules in 4T1 xenograft female Balb/c mice. The molecular network of transforming growth factor β (TGFβ) receptors (TGFRs) plays an important role in the regulation of the epithelial to mesenchymal transition (EMT) in cancer cells. Using 4T1 and MDA-MB-231 cells, we found that fucoidan effectively reverses TGFR-induced EMT morphological changes, upregulates epithelial markers, downregulates mesenchymal markers and decreases the expression of transcriptional repressors Snail, Slug and Twist. Moreover, fucoidan inhibits migration and invasion during the EMT, suggesting the involvement of TGFR-mediated signaling in breast cancer cells. Fucoidan decreases TGFRI and TGFRII proteins and affects downstream signaling molecules, including Smad2/3 phosphorylation and Smad4 expression. In order to elucidate how fucoidan decreases TGFRI and TGFRII proteins in MDA-MB-231 cells, we investigated ubiquitination activity downregulation of TGFRs. It was found that fucoidan enhances proteasome-mediated degradation/ubiquitination of TGFR. This study is the first to identify a novel mechanism for fucoidan antitumor activity, namely regulation of the EMT via modulation of TGFR/Smad-dependent signaling, which leads to an inhibition of breast cancer cell growth in vitro and in vivo. Our current findings indicate that fucoidan is a potential therapeutic agent for breast cancer and acts via an ubiquitin-dependent degradation pathway that affects the TGFR/Smad/Snail, Slug, Twist and EMT axes.

Protective Effects of Fucoidan on Epithelial-Mesenchymal Transition of Retinal Pigment Epithelial Cells and Progression of Proliferative Vitreoretinopathy

“…Recently, several studies suggested that fucoidan could inhibit EMT in various cell types. For instance, Hsu et al found that fucoidan could regulate EMT by modulating TGFR/Smad signaling, which leads to the inhibition of breast cancer metastasis in vitro and in vivo [34]. Yan et al found that fucoidan regulates the miR-29b/DNMT3B/MTSS1 axis and inhibits EMT in human hepatocellular carcinoma cells [35].…”

The in vitro and in vivo effects of the low molecular weight fucoidan on the bone osteogenic differentiation properties

“…The intensity of biological activities of fucoidan varies with species, molecular weight, composition, structure and the route of extraction (Fitton 2011), and its non-animal origin brings particular pharmacological activities (Senni et al 2006). Fucoidan has been well studied for its antitumor (Hsu et al 2013), antiviral (Tengdelius et al 2014), anti-inflammatory (Hwang et al 2011), and anticoagulant (Irhimeh et al 2009) activities. These biological activities are closely related to fucoidan's molecular weight (Yang et al 2008) and sulfate content (Soeda et al 1992).…”

Potencjał fukoidyny jako środka wspomagającego w terapii onkologicznej

“…transforming growth factor β receptor 1/2, TGF-βR1/2), co z kolei przyczynia się do ograniczenia zdolności migracji i inwazji okolicznych tkanek. Ponadto udowodniono, że spadek ekspresji TGFR wynika z jego wzmożonej ubikwityno-zależnej degradacji w proteasomie [50]. Powyższe efekty obserwowano zarówno w warunkach in vivo, jak i in vitro [50].…”

“…Ponadto udowodniono, że spadek ekspresji TGFR wynika z jego wzmożonej ubikwityno-zależnej degradacji w proteasomie [50]. Powyższe efekty obserwowano zarówno w warunkach in vivo, jak i in vitro [50]. Kolejne badanie oceniające skuteczność fukoidyny w hamowaniu przerzutowania zostało przeprowadzone przez Huanga i wsp.…”