Wei W et al. (2021), Sea Cucumber Intestinal Peptide Induces the Apo...

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Front Nutr 2021 Sep 13;8:763692. doi: 10.3389/fnut.2021.763692.

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Sea Cucumber Intestinal Peptide Induces the Apoptosis of MCF-7 Cells by Inhibiting PI3K/AKT Pathway.

Wei W , Fan XM , Jia SH , Zhang XP , Zhang Z , Zhang XJ , Zhang JX , Zhang YW .

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Sea cucumbers are one of many marine echinoderm animals that contain valuable nutrients and medicinal compounds. The bioactive substances in sea cucumbers make them have promising biological and pharmacological properties, including antioxidant, anti-bacterial, and anti-tumor effects. In this study, sea cucumber intestinal peptide (SCIP) is a small molecular oligopeptide (<1,000 Da) extracted from sea cucumber intestines hydrolyzed by alkaline protease. The analysis of amino acid composition showed that hydrophobic amino acids and branched-chain amino acids were rich in SCIP. Nowadays, although increasing studies have revealed the biological functions of the sea cucumber active substances, there are few studies on the function of SCIP. Furthermore, due to the anti-cancer activity being an essential characteristic of sea cucumber active substances, we also investigated the anti-cancer potential and the underlying mechanism of SCIP in vivo and in vitro. The results indicate that SCIP inhibits the growth of MCF-7 tumor cells in zebrafish and increases the apoptosis of human breast cancer MCF-7 cells. Further mechanism studies confirm that SCIP promotes the expression of apoptosis-related proteins and thus promotes the breast cancer cells (MCF-7) apoptosis via inhibition of PI3K/AKT signal transduction pathway.

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	Figure 1. The molecular weight distribution of SCIP investigated by high-performance liquid chromatography (HPLC).
	Figure 2. Sea cucumber intestinal peptide inhibits the growth of tumor cells in zebrafish. The wild-type AB zebrafish do not produce red fluorescence. CM-Dil labeled cells injected into the yolk sac of zebrafish can produce red fluorescence at a certain wavelength. The total fluorescence intensity is positively correlated with the number of cancer cells. (A) Control group; (B) Model group; (C) Capecitabine group, administration of 20 μg/ml capecitabine by water-soluble; (D) Low concentration SCIP group, administration of 27.8 μg/ml SCIP by water-soluble; (E) Middle concentration SCIP group, administration of 83.3 μg/ml SCIP by water-soluble; (F) High concentration SCIP group, administration of 250 μg/ml SCIP by water-soluble. “*” means that the experimental group was significant. On the contrary, the “#” means that the experimental group is not significant.
	Figure 3. SCIP inhibits the proliferation of MCF-7 cells. Cells were synchronized and incubated with SCIP at various concentrations (27.8, 83.3, and 250 μg/ml) for 24, 48, and 72 h, respectively. Then, the cell samples were harvested and subjected to investigate the proliferation of MCF-7 cells by MTT analysis. Each value was expressed as mean ± SD for three independent experiments by GraphPad Prism Software Version 5.0. *p < 0.05 was considered a significant difference when compared with 24 h, and #p < 0.05 was considered a significant difference compared to the low dose group.
	Figure 4. SCIP improves the apoptosis of MCF-7. (I) The apoptosis level of MCF-7 cells was determined by flow cytometry analysis. MCF-7 Cells were cultured and incubated with 20 μg/ml of capecitabine and various concentrations of SCIP (27.8, 83.3, and 250 μg/ml) for 12 h, then, MCF-7 cells were stained with annexin V and PI, and flow cytometry was carried out to detect its apoptosis rate. (II) The expression of apoptosis-related proteins was investigated by western blots. MCF-7 cells were cultured and incubated with 20 μg/ml of capecitabine and various concentrations of SCIP (27.8, 83.3, and 250 μg/ml) for 12 h; After the treatment, the cells were collected to extract the total proteins and performed the western blot analysis to measure the expression of apoptosis proteins. a: Control group, MCF-7 cells were stimulated by PBS; b: Capecitabine group, MCF-7 cells were incubated by 20 μg/ml of capecitabine for 12 h; c: Low dose SCIP group, MCF-7 cells were incubated by 27.8 μg/ml of SCIP for 12 h; d: Moderate dose SCIP group, MCF-7 cells were incubated by 83.3 μg/ml of SCIP for 12 h; f: High dose SCIP group, MCF-7 cells were incubated by 250 μg/ml of SCIP for 12 h.
	Figure 5. SCIP promotes the apoptosis of MCF-7 by activation of PI3K/AKT signaling pathway. (I) MCF-7 cells were treated with various concentrations of SCIP (0, 27.8, 83.3, and 250 μg/ml) for 24 h, then collected the cells to extract the total proteins and western blots were used to investigate the expression of total AKT (t-AKT), p-AKT, t-PI3k, and p-PI3k, respectively (n = 3). (II) MCF-7 cells were pretreated with wortmannin for 1 h, then incubated with SCIP (0, 27.8, 83.3, and 250 μg/ml) for 24 h. After treatment, the MCF-7 cells were harvested to detect the expression of t-AKT, p-AKT, Clv.caspase-9, and Clv.caspase-3 (n = 3).

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