Abstract
BackgroundCancer metastasis is the main cause leading to disease recurrence and high mortality in cancer patients. Therefore, inhibiting metastasis process or killing metastatic cancer cells by inducing apoptosis is of clinical importance in improving cancer patient survival. Previous studies revealed that fucoidan, a fucose-rich polysaccharide isolated from marine brown alga, is a promising natural product with significant anti-cancer activity. However, little is known about the role of endoplasmic reticulum (ER) stress in fucoidan-induced cell apoptosis.Principal FindingsWe reported that fucoidan treatment inhibits cell growth and induces apoptosis in cancer cells. Fucoidan treatments resulted in down-regulation of the glucose regulated protein 78 (GRP78) in the metastatic MDA-MB-231 breast cancer cells, and of the ER protein 29 (ERp29) in the metastatic HCT116 colon cancer cells. However, fucoidan treatment promoted ER Ca2+-dependent calmodulin-dependent kinase II (CaMKII) phosphorylation, Bcl-associated X protein (Bax) and caspase 12 expression in MDA-MB-231 cells, but not in HCT116 cells. In both types of cancer cells, fucoidan activated the phosphorylation of eukaryotic initiation factor 2 alpha (p-eIF2α)\\CCAAT/enhancer binding protein homologous protein (CHOP) pro-apoptotic cascade and inhibited the phosphorylation of inositol-requiring kinase 1 (p-IRE-1)\\X-box binding proteins 1 splicing (XBP-1s) pro-survival cascade. Furthermore, CHOP knockdown prevented DNA damage and cell death induced by fucoidan.Conclusion/SignificanceFucoidan exerts its anti-tumor function by modulating ER stress cascades. Contribution of ER stress to the fucoidan-induced cell apoptosis augments our understanding of the molecular mechanisms underlying its anti-tumour activity and provides evidence for the therapeutic application of fucoidan in cancer.
Highlights
Cancer is a chronic disease with high mortality due to its high metastatic ability and resistance to chemo- and radio-therapy
To determine whether cell apoptosis attributes to the inhibition of cell growth, both types of cells were treated with fucoidan (100 mg/ml) for 3 days and cell apoptosis was assessed by examining the expression of cleaved caspase 3 and transferase-mediated dUTP nick end labelling (TUNEL)
We demonstrate that fucoidan modulates endoplasmic reticulum (ER) stress cascades in cancer cells and the activated CCAAT/enhancer binding protein homologous protein (CHOP) expression is responsible for fucoidan-induced cell apoptosis
Summary
Cancer is a chronic disease with high mortality due to its high metastatic ability and resistance to chemo- and radio-therapy. Developing natural products for cancer therapy is a promising strategy for cancer treatment and prevention. Its anti-tumour activity is exerted by regulating multiple signalling pathways in cancer cells. The in vivo studies demonstrated that fucoidan suppressed tumour growth and significantly diminished lung metastasis of 4T1 breast cancer cells [14,15,16]. These results support the potential development of fucoidan as an anticancer drug. Previous studies revealed that fucoidan, a fucose-rich polysaccharide isolated from marine brown alga, is a promising natural product with significant anti-cancer activity. Little is known about the role of endoplasmic reticulum (ER) stress in fucoidan-induced cell apoptosis
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