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In vivo induction of apoptosis by fucoxanthin, a marine carotenoid, associated with down-regulating STAT3/EGFR signaling in sarcoma 180 (S180) xenografts-bearing mice.

Wang J, Chen S, Xu S, Yu X, Ma D, Hu X, Cao X - Mar Drugs (2012)

Bottom Line: But the precise mechanism by which fucoxanthin exerts anticarcinogenic effects is not yet fully understood.In addition, immunohistochemistry analysis and Western blotting analysis showed that fucoxanthin significantly decreased the expressions of survivin and vascular endothelial growth factor (VEGF).Most importantly, fucoxanthin inhibited the expressions of the epidermal growth factor receptor (EGFR) and STAT3 and phosphorylated STAT3 proteins.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, College of Medicine, Wuhan University of Science and Technology, Wuhan 430065, China. wangj79@hotmail.com

ABSTRACT
Previous in vitro researches have showed that fucoxanthin, a natural carotenoid isolated from sargassum, can inhibit proliferation or induce apoptosis in human neuroblastoma, hepatoma, leukemia, colon carcinoma, prostate cancer or urinary bladder cancer cells. But the precise mechanism by which fucoxanthin exerts anticarcinogenic effects is not yet fully understood. In this study, we performed an in vivo study to investigate the anti-tumor effect and mechanisms of fucoxanthin on xenografted sarcoma 180 (S180) in mice. Results revealed that fucoxanthin significantly inhibited the growth of sarcoma at the dose of 50 or 100 mg/kg. TUNEL analysis showed that the number of positive cells in the fucoxanthin-treated group was higher than that in the control group. Western blotting analysis also revealed the suppressed expression of bcl-2 and enhanced expression of cleaved caspase-3 by fucoxanthin. In addition, immunohistochemistry analysis and Western blotting analysis showed that fucoxanthin significantly decreased the expressions of survivin and vascular endothelial growth factor (VEGF). Most importantly, fucoxanthin inhibited the expressions of the epidermal growth factor receptor (EGFR) and STAT3 and phosphorylated STAT3 proteins. These results indicated that in vivo induction of apoptosis by fucoxanthin is associated with down-regulating STAT3/EGFR signaling in S180 xenografts-bearing mice.

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Expression of epidermal growth factor receptor (EGFR) protein in sarcoma tissue (A,B). (A) Sarcoma sections from different groups were immunohistochemically stained to assay the expressions of EGFR protein. The expression of EGFR -positive cells (black arrow) was down-regulated by fucoxanthin (×200). Slides are representative of 15 animals per group; (B) Tissue homogenates from S180 sarcomas were prepared, and then the expression levels of EGFR protein in sarcoma were confirmed by western blotting. Treatment with fucoxanthin at the dose of 50 and 100 mg/kg obviously reduced EGFR expression compared with model control group. Values are the mean ± SD. *p < 0.05, **p < 0.01 vs. control group.
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marinedrugs-10-02055-f006: Expression of epidermal growth factor receptor (EGFR) protein in sarcoma tissue (A,B). (A) Sarcoma sections from different groups were immunohistochemically stained to assay the expressions of EGFR protein. The expression of EGFR -positive cells (black arrow) was down-regulated by fucoxanthin (×200). Slides are representative of 15 animals per group; (B) Tissue homogenates from S180 sarcomas were prepared, and then the expression levels of EGFR protein in sarcoma were confirmed by western blotting. Treatment with fucoxanthin at the dose of 50 and 100 mg/kg obviously reduced EGFR expression compared with model control group. Values are the mean ± SD. *p < 0.05, **p < 0.01 vs. control group.

Mentions: STAT3 has been reported to be activated by interleukin-6 receptor (IL-6R) or EGFR in carcinomas, which may have important implications for responsiveness to therapeutics targeted at EGFR, IL-6R, or intermediary kinases [38]. EGFR pathway is one of the most dysregulated molecular pathways in human cancers. The activation of EGFR, an ubiquitously expressed transmembrane glycoprotein belonging to the ErbB/HER family of receptor tyrosine kinases, has been found to lead to the rapid phosphorylation of STAT3 on tyrosine 705 and the subsequent activation of STAT3-dependent gene expression [39]. On the other hand, activation of the EGFR pathway increases the production of tumor-derived VEGF that acts on endothelial cells in a paracrine manner to promote angiogenesis [40]. EGFR expression was determined by immunohistochemistry and western blot (Figure 6A,B). There were few positive immunostained cells in CTX positive control group, which was also evidenced by western blot. Treatment with fucoxanthin at the dose of 25, 50 and 100 mg/kg obviously reduced EGFR expression compared with the model control group (p < 0.05, Figure 6B). These data indicated that, consistent with those of STAT3 and VEGF, the expression of EGFR in the tumor tissue was remarkably declined by treatment with fucoxanthin, suggesting that down-regulation of STAT3/EGFR signaling appeared to involve in the in vivo anti-tumor effect and apoptosis induction of fucoxanthin.


In vivo induction of apoptosis by fucoxanthin, a marine carotenoid, associated with down-regulating STAT3/EGFR signaling in sarcoma 180 (S180) xenografts-bearing mice.

Wang J, Chen S, Xu S, Yu X, Ma D, Hu X, Cao X - Mar Drugs (2012)

Expression of epidermal growth factor receptor (EGFR) protein in sarcoma tissue (A,B). (A) Sarcoma sections from different groups were immunohistochemically stained to assay the expressions of EGFR protein. The expression of EGFR -positive cells (black arrow) was down-regulated by fucoxanthin (×200). Slides are representative of 15 animals per group; (B) Tissue homogenates from S180 sarcomas were prepared, and then the expression levels of EGFR protein in sarcoma were confirmed by western blotting. Treatment with fucoxanthin at the dose of 50 and 100 mg/kg obviously reduced EGFR expression compared with model control group. Values are the mean ± SD. *p < 0.05, **p < 0.01 vs. control group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3475273&req=5

marinedrugs-10-02055-f006: Expression of epidermal growth factor receptor (EGFR) protein in sarcoma tissue (A,B). (A) Sarcoma sections from different groups were immunohistochemically stained to assay the expressions of EGFR protein. The expression of EGFR -positive cells (black arrow) was down-regulated by fucoxanthin (×200). Slides are representative of 15 animals per group; (B) Tissue homogenates from S180 sarcomas were prepared, and then the expression levels of EGFR protein in sarcoma were confirmed by western blotting. Treatment with fucoxanthin at the dose of 50 and 100 mg/kg obviously reduced EGFR expression compared with model control group. Values are the mean ± SD. *p < 0.05, **p < 0.01 vs. control group.
Mentions: STAT3 has been reported to be activated by interleukin-6 receptor (IL-6R) or EGFR in carcinomas, which may have important implications for responsiveness to therapeutics targeted at EGFR, IL-6R, or intermediary kinases [38]. EGFR pathway is one of the most dysregulated molecular pathways in human cancers. The activation of EGFR, an ubiquitously expressed transmembrane glycoprotein belonging to the ErbB/HER family of receptor tyrosine kinases, has been found to lead to the rapid phosphorylation of STAT3 on tyrosine 705 and the subsequent activation of STAT3-dependent gene expression [39]. On the other hand, activation of the EGFR pathway increases the production of tumor-derived VEGF that acts on endothelial cells in a paracrine manner to promote angiogenesis [40]. EGFR expression was determined by immunohistochemistry and western blot (Figure 6A,B). There were few positive immunostained cells in CTX positive control group, which was also evidenced by western blot. Treatment with fucoxanthin at the dose of 25, 50 and 100 mg/kg obviously reduced EGFR expression compared with the model control group (p < 0.05, Figure 6B). These data indicated that, consistent with those of STAT3 and VEGF, the expression of EGFR in the tumor tissue was remarkably declined by treatment with fucoxanthin, suggesting that down-regulation of STAT3/EGFR signaling appeared to involve in the in vivo anti-tumor effect and apoptosis induction of fucoxanthin.

Bottom Line: But the precise mechanism by which fucoxanthin exerts anticarcinogenic effects is not yet fully understood.In addition, immunohistochemistry analysis and Western blotting analysis showed that fucoxanthin significantly decreased the expressions of survivin and vascular endothelial growth factor (VEGF).Most importantly, fucoxanthin inhibited the expressions of the epidermal growth factor receptor (EGFR) and STAT3 and phosphorylated STAT3 proteins.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, College of Medicine, Wuhan University of Science and Technology, Wuhan 430065, China. wangj79@hotmail.com

ABSTRACT
Previous in vitro researches have showed that fucoxanthin, a natural carotenoid isolated from sargassum, can inhibit proliferation or induce apoptosis in human neuroblastoma, hepatoma, leukemia, colon carcinoma, prostate cancer or urinary bladder cancer cells. But the precise mechanism by which fucoxanthin exerts anticarcinogenic effects is not yet fully understood. In this study, we performed an in vivo study to investigate the anti-tumor effect and mechanisms of fucoxanthin on xenografted sarcoma 180 (S180) in mice. Results revealed that fucoxanthin significantly inhibited the growth of sarcoma at the dose of 50 or 100 mg/kg. TUNEL analysis showed that the number of positive cells in the fucoxanthin-treated group was higher than that in the control group. Western blotting analysis also revealed the suppressed expression of bcl-2 and enhanced expression of cleaved caspase-3 by fucoxanthin. In addition, immunohistochemistry analysis and Western blotting analysis showed that fucoxanthin significantly decreased the expressions of survivin and vascular endothelial growth factor (VEGF). Most importantly, fucoxanthin inhibited the expressions of the epidermal growth factor receptor (EGFR) and STAT3 and phosphorylated STAT3 proteins. These results indicated that in vivo induction of apoptosis by fucoxanthin is associated with down-regulating STAT3/EGFR signaling in S180 xenografts-bearing mice.

Show MeSH
Related in: MedlinePlus