In Vivo Metabolites of Panaxadiol Inhibit HepG-2 Cell Proliferation by Inducing G1 Arrest and ROS-Mediated Apoptosis

Xu, Lei; Xiao, Shengnan; Lee, Jun Young; Jiang, Hua; Li, Xiaofei; Zhang, Xiaoshu; Zhao, Yanfang

doi:10.1021/acs.jafc.2c04298

Cited by 4 publications

(4 citation statements)

References 24 publications

(45 reference statements)

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“…These findings suggest that CSN5 suppression may partially trigger cellular apoptosis via the direct activation of the ATF4-CHOP pathway. In addition, beyond the apoptosis induced by ER stress, excessive mitochondrial ROS production may precipitate caspase-dependent cellular destruction 45 . This implies that CSN5 intervention might concurrently induce cell apoptosis through two pathways.…”

Section: Discussionmentioning

confidence: 99%

A novel CSN5/CRT O-GlcNAc/ER stress regulatory axis in platinum resistance of epithelial ovarian cancer

Yan,

Ma,

Zhou

et al. 2024

Int. J. Biol. Sci.

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Background: High levels of COP9 signalosome subunit 5 (CSN5) in epithelial ovarian cancer (EOC) are associated with poor prognosis and are implicated in mediating platinum resistance in EOC cells. The underlying mechanisms, however, remained undefined. This study aimed to elucidate the molecular process and identify potential therapeutic targets. Methods: RNA-sequencing was used to investigate differentially expressed genes between platinum-resistant EOC cells with CSN5 knockdown and controls. O-GlcNAc proteomics were employed to identify critical modulators downstream of CSN5. The omics findings were confirmed through qRT-PCR and immunoblotting. In vitro and in vivo experiments assessed the sensitivity of resistant EOCs to platinum. Results: We demonstrated an involvement of aberrant O-GlcNAc and endoplasmic reticulum (ER) stress disequilibrium in CSN5-mediated platinum resistance of EOC. Genetic or pharmacologic inhibition of CSN5 led to tumor regression and surmounted the intrinsic EOC resistance to platinum both in vitro and in vivo. Integration of RNA-sequencing and O-GlcNAc proteomics pinpointed calreticulin (CRT) as a potential target of aberrant O-GlcNAc modification. CSN5 upregulated O-GlcNAc-CRT at T346 to inhibit ER stress-induced cell death. Blocking T346 O-GlcNAc-CRT through CSN5 deficiency or T346A mutation resulted in Ca 2+ disturbances, followed by ER stress overactivation, mitochondrial dysfunction, and ultimately cell apoptosis. Conclusion:This study reveals that CSN5-mediated aberrant O-GlcNAc-CRT acts as a crucial ER stress checkpoint, governing cell fate response to stress, and emphasizes an unrecognized role for the CSN5/CRT O-GlcNAc/ER stress axis in platinum resistance of EOC.

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Section: Discussionmentioning

confidence: 99%

A novel CSN5/CRT O-GlcNAc/ER stress regulatory axis in platinum resistance of epithelial ovarian cancer

Yan,

Ma,

Zhou

et al. 2024

Int. J. Biol. Sci.

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“…Elevated levels of ROS in cells can promote their apoptosis. 15 Green fluorescence indicates the presence of ROS in the cells. 16 They react with biological compounds, leading to metabolic pathway changes, cell membrane peroxidation, oxidative protein modification, and DNA mutations that promote cell or tissue damage.…”

Section: Discussionmentioning

confidence: 99%

“…ROS are highly reactive metabolites produced during regular cellular metabolism. Elevated levels of ROS in cells can promote their apoptosis . Green fluorescence indicates the presence of ROS in the cells .…”

Section: Discussionmentioning

confidence: 99%

Monacolin K Induces Apoptosis of Human Glioma U251 Cells by Triggering ROS-Mediated Oxidative Damage and Regulating MAPKs and NF-κB Pathways

Shi

Huang

et al. 2023

ACS Chem. Neurosci.

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Monacolin K (MK), a polyketo secondary metabolic compound of the mold genus Monascus, can promote the apoptosis of malignant cancer cells, possessing potential antitumor properties. However, its mechanism of action on gliomas remains unclear. Here, we explored and investigated the potential of the monacolin K's antitumor effect on human glioma U251 cells and its possible molecular mechanism. Results showed that the application of 10 μM monacolin K inhibited the proliferation of U251 cells, with an inhibitory rate of up to 53.4%. Additionally, monacolin K induced the generation of reactive oxygen species and activated mitochondria-mediated pathways, including decreased MMP, activation of caspase3/caspase9, decreased Na + /K + -ATPase and Ca 2+ -ATPase activities, and disruption of the antioxidant system, resulting in the disruption of intracellular reduction−oxidation homeostasis. Monacolin K also activated MAPK and NF-κB pathways, upregulating P38 activity and downregulating JNK/ERK/ P65/IκBα expression, ultimately leading to apoptosis of U251 cells. Importantly, monacolin K was not cytotoxic to normal human cells, hUC-MSCs. We concluded that monacolin K can induce apoptosis in U251 cells by triggering ROS-mediated oxidative damage and regulating MAPKs and NF-κB pathways.

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“…Red ginseng is formed by stewing ginseng, during which a large number of ginsenosides undergo hydrolysis, conformational inversion and other changes, forming a series of rare saponins with stronger biological activity and greater advantages in absorption and bioavailability compared with the prototype glycosides [3] (eg. PPD [4], 20(S)-25OCH3-PPD [5] and CK [6]). 20 (S)-Dama-20,25-epoxy-3β,12β,24α-triol (24-OH-PD) is a natural diol dammarane ginsenoside isolated and obtained from red ginseng by our research group for the first time.…”

Section: Introductionmentioning

confidence: 99%

Ginsenoside 24-OH-PD from red ginseng inhibits acute T-lymphocytic leukaemia by activating the mitochondrial pathway

Chen

Zhang

et al. 2023

PLoS ONE

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Ginsenoside 24-hydroxy-ginsengdiol (24-OH-PD), extracted from red ginseng, is a novel diol-type ginsenoside, strongly inhibits the growth of human T-cell acute lymphoblastic leukaemia (T-ALL) CCRF-CEM cells. Our research aimed at investigating the mechanism underlying this inhibition. Cell viability was determined using the cell counting kit-8 (CCK-8) assay, and NOD/SCID mice bearing CCRF-CEM cells were used to verify the therapeutic effect of 24-OH-PD on T-ALL in vivo. We equally analysed pathways related to 24-OH-PD in CCRF-CEM cells using RNA-Seq analysis. Cell apoptosis, reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨm), and mitochondrial permeability transition pore (mPTP) levels were detected by flow cytometry. The activity of caspase3 and caspase9 was detected by enzyme activity detection kits. The expression levels of apoptosis-related proteins and mRNA were determined through western blotting and quantitative reverse-transcription PCR assays (qRT-PCR). CCK-8 assay and animal xenograft experiments confirmed that 24-OH-PD significantly inhibited T-ALL in a dose-dependent manner, both in vivo and in vitro. RNA-Seq results suggest that mitochondria-mediated apoptosis pathway plays an important role in this process. Furthermore, intracellular ROS levels increased, mPTP opened, and ΔΨm decreased following 24-OH-PD treatment. Pretreatment with the antioxidant, NAC, reversed the effects of 24-OH-PD on apoptosis and ROS generation. Moreover, 24-OH-PD treatment increased the expression of Bax and caspase family members, thereby releasing cytochrome c (Cytc) and inducing apoptosis. Our findings showed that, 24-OH-PD induces apoptosis in CCRF-CEM cells by activating the mitochondrial-dependent apoptosis pathway through ROS accumulation. This inhibitory effect implies that 24-OH-PD could be further developed as treatment of T-ALL.

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In Vivo Metabolites of Panaxadiol Inhibit HepG-2 Cell Proliferation by Inducing G1 Arrest and ROS-Mediated Apoptosis

Cited by 4 publications

References 24 publications

A novel CSN5/CRT O-GlcNAc/ER stress regulatory axis in platinum resistance of epithelial ovarian cancer

A novel CSN5/CRT O-GlcNAc/ER stress regulatory axis in platinum resistance of epithelial ovarian cancer

Monacolin K Induces Apoptosis of Human Glioma U251 Cells by Triggering ROS-Mediated Oxidative Damage and Regulating MAPKs and NF-κB Pathways

Ginsenoside 24-OH-PD from red ginseng inhibits acute T-lymphocytic leukaemia by activating the mitochondrial pathway

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