Fucoidan downregulates insulin-like growth factor-I receptor levels in HT-29 human colon cancer cells

Abstract

Fucoidan, a sulfated polysaccharide present in brown seaweed, has demonstrated anticancer activity in lung, breast, liver and colon cells. The insulin-like growth factor (IGF) signaling pathway regulates growth in HT-29 cells through the insulin receptor substrate-1 (IRS-1)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and Ras/Raf/extracellular signal-regulated kinase (ERK) pathways. The aim of the present study was to investigate whether fucoidan downregulates the IGF-IR signaling pathway in HT-29 human colon cancer cells. Fucoidan treatment (0-1,000 µg/ml) was administered for 24 h in HT-29 cells. First, we investigated IRS-1/PI3K/AKT pathway-related protein expression levels following treatment with fucoidan (0-500 µg/ml) using western blot analysis. Fucoidan significantly inhibited the expression of IGF-IR, PTEN, PI3K and AKT as well as their phosphorylated forms (p-IRS-1, p-PI3K and p-AKT). Next, we investigated the effects of fucoidan on Ras/Raf/ERK pathway‑related protein expression levels in HT-29 cells. Fucoidan significantly inhibited the expression of IGF-IR, Shc, Ras, SOS, Raf and MEK. HT-29 cells were then incubated in the presence of fucoidan (0 or 250 µg/ml), and IGF-I (10 nM) was added for 0 to 60 min. Immunoprecipitation (IP) experiments showed that fucoidan inhibited IGF-I-induced phosphorylation of IGF-IR, PI3K, Shc (IP, IGF-IR), and phosphorylated IRS-1 and PI3K (IP, IRS-1) compared to the control group. Western blot analysis showed that fucoidan inhibited the expression of IGF-I-induced p-IGF-IR/IGF-IR and p-AKT/AKT, but not p-ERK/ERK. In conclusion, the inhibition of cell viability by fucoidan in HT-29 cells may be due to the downregulation of IGF-IR signaling through the main IRS-1/PI3K/AKT pathway. Fucoidan also partially impacted Ras/Raf signaling in the Ras/Raf/ERK pathway. Therefore, we suggest that fucoidan may be a suitable candidate chemopreventive agent in HT-29 colon cancer cells.

The Therapeutic Potential of the Anticancer Activity of Fucoidan: Current Advances and Hurdles

“…Thinh et al reported three fucoidan fractions (SmF1, SmF2, and SmF3) extracted from Sargassum mcclurei where all fractions were found to be less cytotoxic and exhibited inhibition of colony formation in colon cancer DLD-1 cells [ 92 ]. HT-29 cell death is induced by administration of fucoidan, the probable reason for which could be the downregulation of IGF-IR signaling via the IRS-1/PI3K/AKT pathway [ 93 ].…”

A comprehensive review on the health benefits and nutritional significance of fucoidan polysaccharide derived from brown seaweeds in human, animals and aquatic organisms

“…Pathway of IGF signalling regulates the growth in colon cancer cells (HT‐29) by the insulin receptor substrate‐1 (IRS‐1)/PI3K/AKT and Ras/Raf/ERK pathways. Kim and Nam (2018) noticed that fucoidan significantly dampened the IGF‐IR, PI3K and AKT, expression and their phosphorylated forms (p‐IRS‐1, p‐PI3K and p‐AKT). In addition to its effectiveness in inhibition of IGF‐I‐induced phosphorylation of IGF‐IR, PI3K, Shc (IP, IGF‐IR) and phosphorylated IRS‐1 and PI3K (IP, IRS‐1) compared with the control.…”

<p>The Natural Product Fucoidan Inhibits Proliferation and Induces Apoptosis of Human Ovarian Cancer Cells: Focus on the PI3K/Akt Signaling Pathway</p>

“…19 In addition, HT-29 colon cancer cell viability was inhibited by fucoidan, possibly due to the downregulation IGF-IR signaling through the IRS-1/PI3K/AKT pathway. 20 As a significant clinical application, fucoidan has been found to improve the sensitivity of lung and breast cancer to chemotherapeutic drugs, which not only reduced the severity of related side effects, but also reduced the economic burden to patients. 10,11 In addition, many studies have reported that fucoidan also plays an important anti-cancer role in other tumors, including prostate cancer, gastric cancer, liver cancer, and large B cell lymphoma.…”