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

Hsu, Hsien Yeh; Lin, Tsai-Yun; Lu, Mei-Kuang; Leng, Pei Ju; Tsao, Shu Ming; Wu, Yu Chung

doi:10.1038/srep44990

Cited by 81 publications

(57 citation statements)

References 49 publications

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“…58,59) Accumulation of ROS production will directly damage mitochondrial coupling with dysfunction of ER. In the present study, bavachin not only activated ER stress but also disrupted mitochondrial function evidenced by depletion of MMP and increased ROS.…”

Section: Discussionmentioning

confidence: 99%

Bavachin Induces Apoptosis through Mitochondrial Regulated ER Stress Pathway in HepG2 Cells

Yang

Tang²,

Hao³

et al. 2018

Biological & Pharmaceutical Bulletin

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As a traditional herbal medicine, the fruits of Psoralea corylifolia L. (Fructus Psoraleae (FP)) have been widely used for the treatment of various skin diseases for hundred years. Recently, the emerging FPinduced toxic effects, especially hepatotoxicity, in clinic are getting the public's attention. However, its exact toxic components and mechanisms underlying remain unclear. Bavachin, one of flavonoids in FP, has been documented as a hepatotoxic substance, and the present study aimed to determine the toxicity caused by bavachin and the possible toxic mechanisms involved using human hepatocellular carcinoma (HepG2) cells. Our results showed that bavachin could significantly inhibited cell proliferation and trigger the endoplasmic reticulum (ER) stress in a dose dependent manner. Downregulating ER stress using tauroursodeoxycholic acid (TUDCA) obvious attenuated bavachin-triggerd cell apoptosis. Then, small interfering RNA (siRNA) knock-down of Mitofusion2 (Mfn2) resulted in a remarkable aggravation of ER stress through the inhibition of the phosphorylation of protein kinase B (Akt). Additionally, suppression of reactive oxygen species (ROS) by ROS Scavenger (N-acetyl-l-cystein (NAC)) also reduced bavachin-induced ER stress. Taken together, our study demonstrated that bavachin-induced ER stress caused cell apoptosis by Mfn2-Akt pathway, and that ROS may participate upstream in this mechanism. Here, we not only provide a new understanding of ROS/ Mfn2/Akt pathway in bavachin-induced cytotoxicity via the ER stress, but also identify a new specific intervention to prevent FP-induced hepatotoxicity in the future.

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Section: Discussionmentioning

confidence: 99%

Bavachin Induces Apoptosis through Mitochondrial Regulated ER Stress Pathway in HepG2 Cells

Yang

Tang²,

Hao³

et al. 2018

Biological & Pharmaceutical Bulletin

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“…To alleviate this stress, autophagy can be triggered as a secondary response [71]. Recently, Hsu et al [72] showed that both commercial fucoidans from Laminaria japonica and F. vesiculosus prevented lung cancer cells via ROS-mediated induction, Chen et al [73] reported that commercial fucoidan from F. vesiculosus inhibited MDA-MB-231 breast cancer cells and HCT116 colon cancer cells by increasing the expression of CHOP (related to ER-stress), and Park et al [74] reported that AGS human gastric adenocarcinoma cells had enhanced autophagy and mitochondrial damage after treatment with commercial fucoidan (undefined source).…”

Section: F Vesiculosus Fucoidan Causes Stress-induced Apoptosis-likementioning

confidence: 99%

Fucoidan Inhibition of Osteosarcoma Cells is Species and Molecular Weight Dependent

et al. 2020

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Fucoidan is a brown algae-derived polysaccharide having several biomedical applications. This study simultaneously compares the anti-cancer activities of crude fucoidans from Fucus vesiculosus and Sargassum filipendula, and effects of low (LMW, 10–50 kDa), medium (MMW, 50–100 kDa) and high (HMW, >100 kDa) molecular weight fractions of S. filipendula fucoidan against osteosarcoma cells. Glucose, fucose and acid levels were lower and sulphation was higher in F. vesiculosus crude fucoidan compared to S. filipendula crude fucoidan. MMW had the highest levels of sugars, acids and sulphation among molecular weight fractions. There was a dose-dependent drop in focal adhesion formation and proliferation of cells for all fucoidan-types, but F. vesiculosus fucoidan and HMW had the strongest effects. G1-phase arrest was induced by F. vesiculosus fucoidan, MMW and HMW, however F. vesiculosus fucoidan treatment also caused accumulation in the sub-G1-phase. Mitochondrial damage occurred for all fucoidan-types, however F. vesiculosus fucoidan led to mitochondrial fragmentation. Annexin V/PI, TUNEL and cytochrome c staining confirmed stress-induced apoptosis-like cell death for F. vesiculosus fucoidan and features of stress-induced necrosis-like cell death for S. filipendula fucoidans. There was also variation in penetrability of different fucoidans inside the cell. These differences in anti-cancer activity of fucoidans are applicable for osteosarcoma treatment.

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“…(−) indicates a negative control using transfection‐free HEK293T cells. Arrows indicate the Bip band, and arrowheads indicate unknown bands that were often detected when using the anti‐Bip antibody (Hsu et al ). (b) Quantification of co‐IP efficiency shown in (a).…”

Section: Resultsmentioning

confidence: 99%

Monitoring the glycosylation of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole‐propionate‐type glutamate receptors using specific antibodies reveals a novel regulatory mechanism of N‐glycosylation occupancy by molecular chaperones in mice

Midorikawa

Takakura

Morise

et al. 2020

Journal of Neurochemistry

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In the mammalian nervous system, protein N-glycosylation plays an important role in neuronal physiology. In this study, we performed a comprehensive N-glycosylation analysis of mouse GluA1, one of the major subunits of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate type glutamate receptor, which possesses six potential N-glycosylation sites in the N-terminal domain. By mass spectrometry-based analysis, we identified the N-glycoforms and semiquantitatively determined the site-specific N-glycosylation occupancy of GluA1. In addition, only the N401-glycosylation site demonstrated incomplete N-glycosylation occupancy. Therefore, we generated a peptide antibody that specifically detects the N401-glycan-free form to precisely quantify N401-glycosylation occupancy. Using this antibody, we clarified that N401 occupancy varies between cell types and increases in an age-dependent manner in mouse forebrains. To address the regulatory mechanism of N401-glycosylation, binding proteins of GluA1 around the N401 site were screened. HSP70 family proteins, including Bip, were identified as candidates. Bip has been known as a molecular chaperone that plays a key role in protein folding in the ER (endoplasmic reticulum). To examine the involvement of Bip in N401-glycosylation, the effect of Bip over-expression on N401 occupancy was evaluated in HEK293T cells, and the results demonstrated Bip increases the N401 glycan-free form by mediating selective prolongation of its protein half-life. Taken together, we propose that the N401-glycosite of GluA1 receives a unique control of modification, and we also propose a novel N-glycosylation occupancy regulatory mechanism by Bip that might be associated with α-amino-3hydroxy-5-methyl-4-isoxazole-propionate receptors function in the brain. K E Y W O R D S AMPA, Bip, glutamate receptor, molecular chaperone, N-glycosylation S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section. How to cite this article: Midorikawa R, Takakura D, Morise J, et al. Monitoring the glycosylation of α-amino-3-hydroxy-5methyl-4-isoxazole-propionate-type glutamate receptors using specific antibodies reveals a novel regulatory mechanism of N-glycosylation occupancy by molecular chaperones in mice. J.

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

Cited by 81 publications

References 49 publications

Bavachin Induces Apoptosis through Mitochondrial Regulated ER Stress Pathway in HepG2 Cells

Bavachin Induces Apoptosis through Mitochondrial Regulated ER Stress Pathway in HepG2 Cells

Fucoidan Inhibition of Osteosarcoma Cells is Species and Molecular Weight Dependent

Monitoring the glycosylation of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole‐propionate‐type glutamate receptors using specific antibodies reveals a novel regulatory mechanism of N‐glycosylation occupancy by molecular chaperones in mice

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