Induction of p53-Independent Apoptosis and G1 Cell Cycle Arrest by Fucoidan in HCT116 Human Colorectal Carcinoma Cells

Park, Hye Young; Park, Shin‐Hyung; Jeong, Jin‐Woo; Yoon, Dahye; Han, Min; Lee, Daesung; Choi, Grace; Yim, Mi‐Jin; Lee, Jeong Min; Kim, Do-Hyung; Kim, Gi‐Young; Choi, Il‐Whan; Kim, Suhkmann; Kim, Heui‐Soo; Cha, Hee‐Jae; Choi, Yung Hyun

doi:10.3390/md15060154

Cited by 60 publications

(37 citation statements)

References 38 publications

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“…This finding is consistent with those of previous studies of colorectal and breast cancer cells. 38,39 On the other hand, flow cytometry and Hoechst staining showed that the number of apoptotic cells had increased significantly following fucoidan treatment with increased expression of the pro-apoptotic protein Bax and decreased expression of the anti-apoptotic protein Bcl-2, suggesting that fucoidan-induced apoptosis may be related to the mitochondria. Therefore, increased expression levels of cleaved caspase-3 and caspase-9 expression, as determined by Western blot analysis were consistent with our expectations.…”

Section: Discussionmentioning

confidence: 99%

<p>The Natural Product Fucoidan Inhibits Proliferation and Induces Apoptosis of Human Ovarian Cancer Cells: Focus on the PI3K/Akt Signaling Pathway</p>

Liu

Yang

Peng

et al. 2020

CMAR

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Objective: Ovarian cancer (OC) is the leading cause of death among gynecological tumors; however, no effective treatment is currently available. Fucoidan, which is extracted from marine algae, has significant anti-cancer effects. The aim of this study was to determine the effects of fucoidan on the proliferation and apoptosis of OC cells through inhibition of the PI3K/Akt signaling pathway. Methods: Human ovarian normal epithelial cells (IOSE80) and human OC cells (SKOV-3, A2780, OVCAR-3, TOV-112D, and Caov-3) were selected to verify the safety of fucoidan at various doses in SKOV-3 and Caov-3 cells as well as a xenograft mouse model using various molecular biology techniques. Results: Fucoidan had no significant effect on normal ovarian epithelial cells, but had significantly inhibited the proliferation of OC cells, induced cell cycle arrest at the G0/G1 phase, increased the proportion of apoptotic cells and expression of pro-apoptotic proteins, and inhibited the expression of PI3K and phosphorylation of Akt, which could be partly rescued by IGF-1. Conclusion: Fucoidan had anti-tumor effects both in vivo and in vitro via a mechanism that is related to the inhibition of the PI3K/Akt signaling pathway.

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Section: Discussionmentioning

confidence: 99%

<p>The Natural Product Fucoidan Inhibits Proliferation and Induces Apoptosis of Human Ovarian Cancer Cells: Focus on the PI3K/Akt Signaling Pathway</p>

Liu

Yang

Peng

et al. 2020

CMAR

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“…In vivo, the anti-cancer response appears to be a combination of enhanced immune function, regulation of checkpoint inhibitor levels [9,10], and a direct cytotoxic activity on cancer cells such as DU-145 human prostate cancer cells [11]. In pre-clinical colon cancer cell models, fucoidans induced both apoptosis and cell cycle arrest, while the exact mechanism for this effect remains unclear [12,13,14,15]. One suggested mode of action involves fucoidan-induced endoplasmic reticulum (ER) stress that induces apoptotic cancer cell death via the activation of unfolded protein response (UPR) pathways [14,16,17].…”

Section: Introductionmentioning

confidence: 99%

Pathway Analysis of Fucoidan Activity Using a Yeast Gene Deletion Library Screen

et al. 2019

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Fucoidan, the sulfated fucose-rich polysaccharide derived from brown macroalgae, was reported to display some anti-cancer effects in in vitro and in vivo models that included apoptosis and cell cycle arrest. The proposed mechanisms of action involve enhanced immune surveillance and direct pro-apoptotic effects via the activation of cell signaling pathways that remain largely uncharacterized. This study aimed to identify cellular pathways influenced by fucoidan using an unbiased genetic approach to generate additional insights into the anti-cancer effects of fucoidan. Drug–gene interactions of Undaria pinnatifida fucoidan were assessed by a systematic screen of the entire set of 4,733 halpoid Saccharomyces cerevsiae gene deletion strains. Some of the findings were confirmed using cell cycle analysis and DNA damage detection in non-immortalized human dermal fibroblasts and colon cancer cells. The yeast deletion library screen and subsequent pathway and interactome analysis identified global effects of fucoidan on a wide range of eukaryotic cellular processes, including RNA metabolism, protein synthesis, sorting, targeting and transport, carbohydrate metabolism, mitochondrial maintenance, cell cycle regulation, and DNA damage repair-related pathways. Fucoidan also reduced clonogenic survival, induced DNA damage and G1-arrest in colon cancer cells, while these effects were not observed in non-immortalized human fibroblasts. Our results demonstrate global effects of fucoidan in diverse cellular processes in eukaryotic cells and further our understanding about the inhibitory effect of Undaria pinnatifida fucoidan on the growth of human cancer cells.

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“…Recent data indicate that fucoidan triggers G1 phase arrest and apoptosis in HCT116 colon cancer cells through a p53-independent pathway. In particular, it has been suggested that fucoidan is able to enhance p21 expression at transcriptional level in a p53-independent manner (50). IGF-I signaling is strongly associated with cell growth and has a significant role in ribosome biogenesis by regulating the expression of proteins directly involved in the processing of ribosomal subunits and p53-mediated regulation of cell cycle progression (51).…”

Section: Discussionmentioning

confidence: 99%

Fucoidan downregulates insulin-like growth factor-I receptor levels in HT-29 human colon cancer cells

Kim

Nam

2018

Oncol Rep

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Fucoidan, a sulfated polysaccharide present in brown seaweed, has demonstrated anticancer activity in lung, breast, liver and colon cells. The insulin-like growth factor (IGF) signaling pathway regulates growth in HT-29 cells through the insulin receptor substrate-1 (IRS-1)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and Ras/Raf/extracellular signal-regulated kinase (ERK) pathways. The aim of the present study was to investigate whether fucoidan downregulates the IGF-IR signaling pathway in HT-29 human colon cancer cells. Fucoidan treatment (0-1,000 µg/ml) was administered for 24 h in HT-29 cells. First, we investigated IRS-1/PI3K/AKT pathway-related protein expression levels following treatment with fucoidan (0-500 µg/ml) using western blot analysis. Fucoidan significantly inhibited the expression of IGF-IR, PTEN, PI3K and AKT as well as their phosphorylated forms (p-IRS-1, p-PI3K and p-AKT). Next, we investigated the effects of fucoidan on Ras/Raf/ERK pathway‑related protein expression levels in HT-29 cells. Fucoidan significantly inhibited the expression of IGF-IR, Shc, Ras, SOS, Raf and MEK. HT-29 cells were then incubated in the presence of fucoidan (0 or 250 µg/ml), and IGF-I (10 nM) was added for 0 to 60 min. Immunoprecipitation (IP) experiments showed that fucoidan inhibited IGF-I-induced phosphorylation of IGF-IR, PI3K, Shc (IP, IGF-IR), and phosphorylated IRS-1 and PI3K (IP, IRS-1) compared to the control group. Western blot analysis showed that fucoidan inhibited the expression of IGF-I-induced p-IGF-IR/IGF-IR and p-AKT/AKT, but not p-ERK/ERK. In conclusion, the inhibition of cell viability by fucoidan in HT-29 cells may be due to the downregulation of IGF-IR signaling through the main IRS-1/PI3K/AKT pathway. Fucoidan also partially impacted Ras/Raf signaling in the Ras/Raf/ERK pathway. Therefore, we suggest that fucoidan may be a suitable candidate chemopreventive agent in HT-29 colon cancer cells.

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Induction of p53-Independent Apoptosis and G1 Cell Cycle Arrest by Fucoidan in HCT116 Human Colorectal Carcinoma Cells

Cited by 60 publications

References 38 publications

<p>The Natural Product Fucoidan Inhibits Proliferation and Induces Apoptosis of Human Ovarian Cancer Cells: Focus on the PI3K/Akt Signaling Pathway</p>

<p>The Natural Product Fucoidan Inhibits Proliferation and Induces Apoptosis of Human Ovarian Cancer Cells: Focus on the PI3K/Akt Signaling Pathway</p>

Pathway Analysis of Fucoidan Activity Using a Yeast Gene Deletion Library Screen

Fucoidan downregulates insulin-like growth factor-I receptor levels in HT-29 human colon cancer cells

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