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Oncol Rep
2020 Aug 01;442:469-476. doi: 10.3892/or.2020.7614.
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Sea cucumber Cucumaria frondosa fucoidan inhibits osteosarcoma adhesion and migration by regulating cytoskeleton remodeling.
Zhang M
,
Chen L
,
Liu Y
,
Chen M
,
Zhang S
,
Kong D
.
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Osteosarcoma (OS) has been demonstrated to be difficult to cure due to its potently malignant metastasis. Therefore, new therapeutic approaches blocking the metastatic potential of OS are urgently required to improve the outcomes for OS patients. In the present study, the anti‑metastatic capacity of sea cucumber (Cucumaria frondosa) fucoidan (Cf‑Fuc) was evaluated on osteosarcoma cells by cell adhesion assay, Transwell assay and U2OS cell migration assay. The underlying mechanism on the dynamic remodeling of the cytoskeleton was also explored. The present data indicated that Cf‑Fuc could block the U2OS osteosarcoma cell adhesion to fibronectin and significantly inhibit U2OS cell migration. Cf‑Fuc greatly impaired the migration capacity of U2OS cells, and the migrated distance and velocity of Cf‑Fuc‑treated cells were markedly reduced. Also, Cf‑Fuc could impair the dynamic remodeling of the cytoskeleton possibly by suppressing the phosphorylation of focal adhesion kinase and paxillin, as well as the activation of the Rac1/PAK1/LIMK1/cofilin signaling axis. Collectively, the present findings provide a novel therapeutic potential of C. frondosa fucoidan for osteosarcoma metastasis.
Figure 1. Cytotoxic effect of Cf-Fuc on U2OS cells. Data are expressed as the mean ± SD. *P<0.05 vs. the control group. Cf-Fuc, Cucumaria frondosa fucoidan.
Figure 2. Cf-Fuc inhibits U2OS cell adhesion. U2OS cells were seeded into 96-well plates pre-coated with fibronectin to assess adhesion at indicated time-points (0.5, 1, 2 and 4 h). The adherent cells were fixed and then stained with crystal violet. The dye was quantified using a microplate reader. Cf-Fuc, Cucumaria frondosa fucoidan.
Figure 3. Transwell assay. U2OS cells incubated with or without Cf-Fuc were placed in Transwell inserts. The migrated cells were then fixed and stained with crystal violet. Migrated cells were counted in five random fields. Representative images are presented and data are expressed as the mean ± SD. *P<0.05, **P<0.01 vs. the control group. Cf-Fuc, Cucumaria frondosa fucoidan.
Figure 4. Effect of Cf-Fuc on U2OS cell migration tracks demonstrated by wind-rose plots. Cf-Fuc, Cucumaria frondosa fucoidan.
Figure 5. Effect of Cf-Fuc on the velocity of U2OS cells. ***P<0.001 vs. the control group. Cf-Fuc, Cucumaria frondosa fucoidan.
Figure 6. Effect of Cf-Fuc on actin polymerization in U2OS cells. U2OS cells were seeded into 24-well plates pre-coated with fibronectin, and then treated with or without Cf-Fuc. F-actin was calculated by measuring the fluorescence of extracted rhodamine phalloidin with a fluorescence microplate reader. Bar graphs indicate the changes in F-actin content expressed as a relative fold change in the mean fluorescence intensity of the cells at time 0. Data are presented as the mean ± SD. Cf-Fuc, Cucumaria frondosa fucoidan.
Figure 7. Cf-Fuc inhibits the phosphorylation of FAK and paxillin. (A) U2OS cells were seeded into 6-well plates pre-coated with fibronectin and allowed to adhere for 4 h. The total and phosphorylated proteins were detected by western blotting. The blots for GAPDH demonstrated the equal loading. The quantitative analysis of (B) p-FAK/total FAK and (C) p-paxillin/total paxillin were determined by ImageJ software. Data are presented as the mean ± SD. **P<0.01, ***P<0.001 vs. the control. Cf-Fuc, Cucumaria frondosa fucoidan.
Figure 8. Effect of Cf-Fuc on Rac1 activation in U2OS cells. (A) Rac1 activation assay. (B) Quantitative analysis of Rac1 activation. Data are presented as the mean ± SD. ***P<0.001 vs. the control group. Cf-Fuc, Cucumaria frondosa fucoidan; Rac1, Ras-related C3 botulinum toxin substrate 1.
Figure 9. Cf-Fuc impacts the PAK1/LIMK1/cofilin signaling axis in U2OS cells. (A) The total and phosphorylated PAK1, LIMK1, and cofilin were determined by immunoblotting. The blots for GAPDH demonstrated the equal loading. (B) Quantitative analysis was determined by ImageJ. Data are presented as the mean ± SD. *P<0.05, **P<0.01, ***P<0.001 vs. the control group. Cf-Fuc, Cucumaria frondosa fucoidan; PAK1, p21-activated kinase 1; LIMK1, LIM domain kinase 1.
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