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Biomed Pharmacother. 2017 Oct;94:898-908. doi: 10.1016/j.biopha.2017.08.013. Epub 2017 Aug 12.

Caspase-dependent and caspase-independent induction of apoptosis in breast cancer by fucoidan via the PI3K/AKT/GSK3β pathway in vivo and in vitro.

Author information

1
Department of Biochemistry and Molecular Biology, Basic Medical College, Qingdao University of Medicine, 38 Dengzhou Road, Qingdao, 266021, PR China.
2
Department of Gynaecology, The Affiliated Hospital of Qingdao University, PR China.
3
Master of economics, Qingdao Haixi City Development Ltd, PR China.
4
The Institute of Human Nutrition, Qingdao University of Medicine, PR China. Electronic address: lianghuiyxb@163.com.
5
Master of medicine, Oncology Department, The Affiliated Hospital of Qingdao University, PR China.
6
Department of Immunology, Basic Medical College, Qingdao University of Medicine, PR China.
7
Department of Biochemistry and Molecular Biology, Basic Medical College, Qingdao University of Medicine, 38 Dengzhou Road, Qingdao, 266021, PR China; Medical undergraduate, Qingdao University of Medicine, PR China.

Abstract

Purpose Fucoidan, a complex, sulfated polysaccharide obtained from brown seaweed, exerted anticancer activity through the down-regulation of β-catenin signaling in mouse breast cancer cells in our previous study. This study examines the anti-cancer effects of fucoidan as well as its underlying molecular mechanisms in the human triple negative breast cancer (TNBC) cell line and in 7,12-dimethylbenz[a]anthracene (DMBA)-induced experimental mammary carcinogenesis in rats. Methods in vitro studies, fluorescent staining, flow cytometry and Western blotting were performed to analyze apoptosis and protein expression in human breast cancer MDA-MB-231 cells. In vivo intervention experiments were conducted with Sprague Dawley (SD) rats with DMBA-induced breast cancer. Tumor volumes and weights were measured. Results in vitro fucoidan treatment inhibited proliferation and induced apoptosis in MDA-MB-231 cells. Western blotting detected that Cyt C and Smac were released into the cell cytoplasm and that caspase-3 and caspase-9 were activated in MDA-MB-231 cells. The levels of AIF and EndoG were significantly increased in the cytoplasm and in the nuclei by fucoidan. These data show that fucoidan induced caspase-dependent and caspase-independent apoptosis. Moreover, fucoidan treatment down-regulated the expression of Bid, Bcl-2 and Bcl-xl and up-regulated the level of Bax. In vivo, fucoidan supplementation decreased the mean tumor weight.

DISCUSSION:

Results from the in vivo and in vitro experiments both showed that fucoidan decreased the levels of p-PI3K, p-AKT and p-GSK-3β (Ser9) in breast cancer. The level of β-catenin was also decreased. These results suggest that fucoidan can inhibit MDA-MB-231 human breast cancer cells and DMBA-induced tumors in rats by down-regulating the PI3 K/AKT/GSK3β pathway. This study provides experimental evidence that elucidates the mechanism of antitumor effect of fucoidan and clarifies the mechanism of the effect of fucoidan on the regulation of β-catenin.

KEYWORDS:

(GSK-3β); 7,12-Dimethylbenz[a]anthracene (DMBA); Breast cancer; Caspase-dependent apoptosis; Caspase-independent apoptosis; Fucoidan; Glycogen synthase kinase 3β

PMID:
28810530
DOI:
10.1016/j.biopha.2017.08.013
[Indexed for MEDLINE]

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