Inhibition of Oxidative Stress-Elicited AKT Activation Facilitates PPARγ Agonist-Mediated Inhibition of Stem Cell Character and Tumor Growth of Liver Cancer Cells

Liu, Lanlan; Yang, Zhaojuan; Xu, Yu; Li, Jingyi; Xu, Dongxu; Zhang, Li; Sun, Jiabin; Xia, Shunren; Zou, Feiyan; Liu, Yongzhong

doi:10.1371/journal.pone.0073038

Cited by 27 publications

(20 citation statements)

References 47 publications

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“…389 The PPARγ/NF-κB pathway promotes M2 polarization of macrophages to prevent cell death in ovarian CSCs 4.390 PPARγ activation promotes expression of its target gene PTEN to inhibit PI3K/Akt/ mTOR signaling, which stunts self-renewal, tumorigenicity, and metastasis in cervical CSCs, glioblastoma stem cells, and liver CSCs. 391,392 However, combined expression of Dnmt3a and Dnmt3b inhibits PPARγ expression by direct methylation of its promoter in squamous carcinomas. 393 PPARs are also closely related to the metabolism of CSCs.…”

Section: Major Signaling Pathways In Cscsmentioning

confidence: 99%

Targeting cancer stem cell pathways for cancer therapy

Yang

Shi

Zhao

et al. 2020

Sig Transduct Target Ther

1,113

998

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Since cancer stem cells (CSCs) were first identified in leukemia in 1994, they have been considered promising therapeutic targets for cancer therapy. These cells have self-renewal capacity and differentiation potential and contribute to multiple tumor malignancies, such as recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance. The biological activities of CSCs are regulated by several pluripotent transcription factors, such as OCT4, Sox2, Nanog, KLF4, and MYC. In addition, many intracellular signaling pathways, such as Wnt, NF-κB (nuclear factor-κB), Notch, Hedgehog, JAK-STAT (Janus kinase/signal transducers and activators of transcription), PI3K/AKT/mTOR (phosphoinositide 3-kinase/AKT/mammalian target of rapamycin), TGF (transforming growth factor)/SMAD, and PPAR (peroxisome proliferator-activated receptor), as well as extracellular factors, such as vascular niches, hypoxia, tumor-associated macrophages, cancer-associated fibroblasts, cancer-associated mesenchymal stem cells, extracellular matrix, and exosomes, have been shown to be very important regulators of CSCs. Molecules, vaccines, antibodies, and CAR-T (chimeric antigen receptor T cell) cells have been developed to specifically target CSCs, and some of these factors are already undergoing clinical trials. This review summarizes the characterization and identification of CSCs, depicts major factors and pathways that regulate CSC development, and discusses potential targeted therapy for CSCs.Signal Transduction and Targeted Therapy (2020) 5:8; https://doi.

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Section: Major Signaling Pathways In Cscsmentioning

confidence: 99%

Targeting cancer stem cell pathways for cancer therapy

Yang

Shi

Zhao

et al. 2020

Sig Transduct Target Ther

1,113

998

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“…An increase in intracellular ROS levels activates tumorigenesis-associated pathways including the MAPK, NF-κB, and Akt pathways. 26,27 To examine whether ROS are the upstream activators of Akt, NF-κB, and Stat3 pathways in GC cells, we treated cells with the anti-oxidant NAC. NAC not only blocked intracellular ROS accumulation but also suppressed the activation of Akt-mTOR, Stat3, and IκBα in GC cells (Figure 7).…”

Section: Ros Accumulation Causes the Activation Of Akt Stat3 And Iκmentioning

confidence: 99%

<p>Aloin Inhibits the Proliferation and Migration of Gastric Cancer Cells by Regulating NOX2–ROS-Mediated Pro-Survival Signal Pathways</p>

Wang¹,

Tang²,

Wang³

et al. 2020

DDDT

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Background: Aloin has been reported to have many pharmacological effects including antiinflammatory, anti-oxidant and anti-tumour activities. However, the precise molecular mechanisms underlying the anti-tumour properties of aloin are yet to be elucidated. Methods: HGC-27 and BGC-823 gastric cancer cells were treated with aloin. EdU and colony formation assays were used to detect the proliferation ability of cells. The migration of cells was detected using wound healing and transwell assays. Western blotting was used to detect the levels of cyclinD1, cyclin E1, MMPs, N-cadherin, E-cadherin and NOX2. The phosphorylation of Akt, mTOR, P70S6K, S6, Src, stat3 and IκBα were also detected by Western blotting. Flow cytometry was used to detect the cell cycle distribution.The location of p65 in cells was determined by using a confocal microscopy assay. The total amounts of ROS present in cells were measured using an ROS assay kit. Results: Here, we found that aloin inhibited the proliferation and migration of HGC-27 and BGC-823 gastric cancer cells using a combination of EdU, colony formation, wound healing and transwell assays. Further investigations revealed that aloin decreased the protein expression levels of cyclin D1, N-cadherin, and the matrix metalloproteinases (MMP)-2 and MMP-9; increased E-cadherin expression in a dose-dependent manner; inhibited reactive oxygen species (ROS) generation; and mediated the activation of Akt-mTOR, signal transducer and activator of transcription-3 (Stat3), and NF-κB signalling pathways. Our results also indicated that aloin is able to attenuate the expression levels of the two regulatory proteins of nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2), p47 phox and p22 phox , but had no effect on the level of gp91 phox. N-acetylcysteine treatment of gastric cancer cells inhibited ROS production and Akt-mTOR, Stat3, and IκBα phosphorylation. Taken together, our data suggest that aloin inhibits the proliferation and migration of gastric cancer cells by downregulating NOX2-ROS-mediated activation of the Akt-mTOR, Stat3, and NF-κB signalling pathways. Conclusion: Our findings suggest a potential role for aloin in the prevention of gastric cancer cell proliferation and migration and provide novel insights into the anti-cancer properties of aloin.

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“…In terms of neurodegeneration, protein S ‐nitrosylation has been reported to be involved in redox‐mediated post‐translational modification of proteins and causes synaptic damage and brain cell death . Recent studies from others and ourselves have found that the most common downstream targets of Nox2‐derived ROS are mitogen‐activated protein kinases (MAPKs), such as the extracellular signal‐regulated kinase (ERK), c‐Jun N‐terminal kinase (JNK) and p38 MAPK ; protein kinase B ; phosphoinositide 3‐kinase ; nuclear factor κB (NFκB) ; TNFα receptor‐associated factor 4 ; and signalling molecules involved in cell apoptosis, such as p21 cip1 and p53 .…”

Section: Mechanism Of Nox2 Activation and The Principle Of Nox2 Redoxmentioning

confidence: 99%

Oxidative stress, redox signalling and endothelial dysfunction in ageing‐related neurodegenerative diseases: a role of NADPH oxidase 2

Cahill-Smith

2014

Brit J Clinical Pharma

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Chronic oxidative stress and oxidative damage of the cerebral microvasculature and brain cells has become one of the most convincing theories in neurodegenerative pathology. Controlled oxidative metabolism and redox signalling in the central nervous system are crucial for maintaining brain function; however, excessive production of reactive oxygen species and enhanced redox signalling damage neurons. While several enzymes and metabolic processes can generate intracellular reactive oxygen species in the brain, recently an O2−‐generating enzyme, NADPH oxidase 2 (Nox2), has emerged as a major source of oxidative stress in ageing‐related vascular endothelial dysfunction and neurodegenerative diseases. The currently available inhibitors of Nox2 are not specific, and general antioxidant therapy is not effective in the clinic; therefore, insights into the mechanism of Nox2 activation and its signalling pathways are needed for the discovery of novel drug targets to prevent or treat these neurodegenerative diseases. This review summarizes the recent developments in understanding the mechanisms of Nox2 activation and redox‐sensitive signalling pathways and biomarkers involved in the pathophysiology of the most common neurodegenerative diseases, such as ageing‐related mild cognitive impairment, Alzheimer's disease and Parkinson's disease.

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Inhibition of Oxidative Stress-Elicited AKT Activation Facilitates PPARγ Agonist-Mediated Inhibition of Stem Cell Character and Tumor Growth of Liver Cancer Cells

Cited by 27 publications

References 47 publications

Targeting cancer stem cell pathways for cancer therapy

Targeting cancer stem cell pathways for cancer therapy

<p>Aloin Inhibits the Proliferation and Migration of Gastric Cancer Cells by Regulating NOX2–ROS-Mediated Pro-Survival Signal Pathways</p>

Oxidative stress, redox signalling and endothelial dysfunction in ageing‐related neurodegenerative diseases: a role of NADPH oxidase 2

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