The effects of fucodian on senescence are controlled by the p16INK4a-pRb and p14Arf-p53 pathways in hepatocellular carcinoma and hepatic cell lines

Min, EunYoung; Kim, In‐Hye; Lee, Jungim; Kim, Eun Young; Choi, Youn‐Hee; Nam, Taek‐Jeong

doi:10.3892/ijo.2014.2426

Cited by 39 publications

(30 citation statements)

References 47 publications

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“…In our study, we found that fucoidan treatment increases the proportions of lung cancer cells in G1 phases and the results are comparable to those of another reports3637. Several transducing signal pathways involved in fucoidan-mediated cell cycle arrest have been proposed, such as fucoidan activation of the AKT signaling pathway36 and activation of p16INK4a-Rb and p14Arf-p53 pathways37.…”

Section: Discussionsupporting

confidence: 90%

Fucoidan induces Toll-like receptor 4-regulated reactive oxygen species and promotes endoplasmic reticulum stress-mediated apoptosis in lung cancer

Hsu

Lin

et al. 2017

Sci Rep

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Fucoidan, a sulfated polysaccharide extracted from brown algae, exhibits anti-cancer activity. However, the effects and mechanism of fucoidan-induced apoptosis via endoplasmic reticulum (ER) stress is unclear. In this study, we demonstrated that fucoidan prevents tumorigenesis and reduces tumor size in LLC1-xenograft male C57BL/6 mice. Fucoidan induces an ER stress response by activating the PERK-ATF4-CHOP pathway, resulting in apoptotic cell death in vitro and in vivo. Furthermore, ATF4 knockdown abolishes fucoidan-induced CHOP expression and rescues cell viability. Specifically, fucoidan increases intracellular reactive oxygen species (ROS), which increase ATF4 and CHOP in lung cancer cells. Using the ROS scavenger N-acetyl-l-cysteine (NAC), we found that ROS generation is involved in fucoidan-induced ER stress-mediated apoptosis. Moreover, via Toll-like receptor 4 (TLR4) knockdown, we demonstrated that fucoidan-induced ROS and CHOP expression were attenuated. Our study is the first to identify a novel mechanism for the antitumor activity of fucoidan. We showed that fucoidan inhibits tumor viability by activating the TLR4/ROS/ER stress axis and the downstream PERK-ATF4-CHOP pathway, leading to apoptosis and suppression of lung cancer cell progression. Together, these results indicate that fucoidan is a potential preventive and therapeutic agent for lung cancer that acts via activation of ROS-dependent ER stress pathways.

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Section: Discussionsupporting

confidence: 90%

Fucoidan induces Toll-like receptor 4-regulated reactive oxygen species and promotes endoplasmic reticulum stress-mediated apoptosis in lung cancer

Hsu

Lin

et al. 2017

Sci Rep

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“…These stressors also trigger DNA damage (cellular responses to such damages are regulated by either ATM-Chk2 or ATR-Chk1 pathways) and transactivate p53 and p21 CIP1 . Moreover, p21 CIP1 protein levels may lead to the inhibition of Cdk4/6 activity, which contribute to the G1 arrest or senescence [33,34].…”

Section: Introductionmentioning

confidence: 99%

Role of p53 in the Regulation of Cellular Senescence

et al. 2020

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The p53 transcription factor plays a critical role in cellular responses to stress. Its activation in response to DNA damage leads to cell growth arrest, allowing for DNA repair, or directs cellular senescence or apoptosis, thereby maintaining genome integrity. Senescence is a permanent cell-cycle arrest that has a crucial role in aging, and it also represents a robust physiological antitumor response, which counteracts oncogenic insults. In addition, senescent cells can also negatively impact the surrounding tissue microenvironment and the neighboring cells by secreting pro-inflammatory cytokines, ultimately triggering tissue dysfunction and/or unfavorable outcomes. This review focuses on the characteristics of senescence and on the recent advances in the contribution of p53 to cellular senescence. Moreover, we also discuss the p53-mediated regulation of several pathophysiological microenvironments that could be associated with senescence and its development.Biomolecules 2020, 10, 420 2 of 16 focus on the p53-dependent senescence signaling pathways involved with different stages of senescence and with a consideration for the associated key biomarkers. We also provide an overview on the regulation of p53-mediated cellular senescence in the context of different pathophysiological conditions. Senescence as Cellular Response to StressCellular senescence is defined as a cell state characterized by prolonged and generally irreversible cell-cycle arrest [14] and the acquisition of different phenotypic alterations, including morphological changes, chromatin remodeling, metabolic reprogramming, and secretion of pro-inflammatory factors or SASP (senescence associated secretory phenotypes). These latter count cytokines, growth factors, proteases, and non-soluble extracellular matrix proteins [15]. All these features ultimately limit the replication of both old and damaged cells. Upon physiological conditions, proliferating cells commit to a regular cell cycle [15,16]. On the other hand, both physiological aging, characterized by telomere shortening, and long-term chronic stress, which impairs genomic integrity and stability, could lead to the activation of the senescence pathway [17]. In this sense, the senescence can be viewed as an adaptative response of cells and organisms when exposed to certain unfavorable environmental conditions.Stressors include both intrinsic factors, such as oxidative damage, telomere attrition, hyperproliferation, oncogene activation, and environmental sources, including UV-light, γ-irradiation, and chemotherapeutic drugs [18,19]. Regardless of their origin, the stress factors trigger DNA damage responses (DDR) in the affected cells, which can result in different outcomes, depending on the cell type and the extent of the damage [20]. Mild DNA damage normally induces cell cycle arrest, while severe injury can activate the senescence program or the death programs; the latter includes apoptosis, mitotic catastrophe, autophagy, and necrosis [21].p53 plays a pivotal role in determining the fate of th...

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“…In this study, we showed that fucoidan suppressed proliferation, but not apoptosis, in HLF cells. In contrast, previous studies reported that fucoidan induces apoptosis in several human HCC cell lines, including HepG2, Huh7 and SMMC-7721 cells (9,11,13,14). It is unclear why fucoidan did not induce apoptosis in HLF cells; however, one possibility is that there are different phenotypes between HCC cell lines.…”

Section: Discussionmentioning

confidence: 76%

“…Furthermore, fucoidan exerts anticancer activity and is reported to inhibit the proliferation of colon, breast and prostate cancer cell lines (6)(7)(8). Although fucoidan suppresses HCC proliferation, most of the cell lines used in previous studies, including HepG2 and Huh-7 cells, were well-differentiated (9)(10)(11)(12)(13)(14). Thus, the anticancer activity of fucoidan against poorly differentiated HCC cells, such as the HLF cell line, remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Effects of fucoidan on proliferation, AMP-activated protein kinase, and downstream metabolism- and cell cycle-associated molecules in poorly differentiated human hepatoma HLF cells

Kawaguchi

Hayakawa

Koga

et al. 2015

International Journal of Oncology

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Survival rates are low in patients with poorly differentiated hepatocellular carcinoma (HCC). Fucoidan, a sulfated polysaccharide derived from brown seaweed, has anticancer activity; however, the effects of fucoidan on poorly differentiated HCC remain unclear. In this study, we investigated the effects of fucoidan on AMP-activated protein kinase (AMPK), a proliferation regulator, and its downstream metabolism- and cell cycle-related molecules in a poorly differentiated human hepatoma HLF cell line. HLF cells were treated with fucoidan (10, 50, or 100 µg/ml; n=4) or phosphate buffered saline (control; n=4) for 96 h. Proliferation was evaluated by counting cells every 24 h. AMPK, TSC2, mTOR, GSK3β, acetyl-CoA carboxylase (ACC), ATP-citrate lyase, p53, cyclin D1, cyclin-dependent kinase (CDK) 4, and CDK6 expression and/or phosphorylation were examined by immunoblotting 24 h after treatment with 100 µg/ml fucoidan. Cell cycle progression was analyzed by fluorescence-activated cell sorter 48 h after treatment. Treatment with 50 or 100 µg/ml fucoidan significantly and dose- and time-dependently suppressed HLF cell proliferation (P<0.0001). Fucoidan induced AMPK phosphorylation on Ser172 24 h after treatment. Although no differences were seen in expression and phosphorylation levels of TSC2, mTOR, GSK3β, ATP-citrate lyase, and p53 between the control and fucoidan-treated HLF cells, fucoidan induced ACC phosphorylation on Ser79. Moreover, fucoidan decreased cyclin D1, CDK4 and CDK6 expression 24 h after treatment. Furthermore, HLF cells were arrested in the G1/S phase 48 h after fucoidan treatment. We demonstrated that fucoidan suppressed HLF cell proliferation with AMPK phosphorylation. We showed that fucoidan phosphorylated ACC and downregulated cyclin D1, CDK4 and CDK6 expression. Our findings suggest that fucoidan inhibits proliferation through AMPK-associated suppression of fatty acid synthesis and G1/S transition in HLF cells.

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The effects of fucodian on senescence are controlled by the p16INK4a-pRb and p14Arf-p53 pathways in hepatocellular carcinoma and hepatic cell lines

Cited by 39 publications

References 47 publications

Fucoidan induces Toll-like receptor 4-regulated reactive oxygen species and promotes endoplasmic reticulum stress-mediated apoptosis in lung cancer

Fucoidan induces Toll-like receptor 4-regulated reactive oxygen species and promotes endoplasmic reticulum stress-mediated apoptosis in lung cancer

Role of p53 in the Regulation of Cellular Senescence

Effects of fucoidan on proliferation, AMP-activated protein kinase, and downstream metabolism- and cell cycle-associated molecules in poorly differentiated human hepatoma HLF cells

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