scholarly journals Autophagy-Induced HDAC6 Activity During Hypoxia Regulates Mitochondrial Energy Metabolism Through the β-Catenin/COUP-TFII Axis in Hepatocellular Carcinoma Cells

2021 ◽  
Vol 11 ◽  
Author(s):  
Xiaoyu Yan ◽  
Xianzhi Qu ◽  
Buhan Liu ◽  
Yuanxin Zhao ◽  
Long Xu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Energy Metabolism ◽  
Oxygen Sensor ◽  
Nuclear Translocation ◽  
Driving Forces ◽  
Mitochondrial Energy Metabolism ◽  
Selective Degradation ◽  
Cellular Oxygen ◽  
Poor Outcomes ◽  
Hcc Cells

Hypoxia is one of the main driving forces that results in poor outcomes and drug resistance in hepatocellular carcinoma (HCC). As the critical cellular oxygen sensor, mitochondria respond to hypoxic stress by sending retrograde signals to the nucleus that initiate adaptive metabolic responses and maintain the survival of HCC cells. Increasing evidence suggested autophagy contributes to sustain mitochondrial metabolic and quality control. Understanding how mitochondria communicate with the nucleus and alter transcription may provide promising targets for HCC treatment. In this study, we found mitochondrial undergoes selective degradation by autophagy under hypoxia. Furthermore, autophagy-activated HDAC6 not only promoted the nuclear translocation of β-catenin but also increased the affinity of β-catenin to the transcription repressor chicken ovalbumin upstream promoter-transcription factor 2 (COUP-TF II), which suppressed mitochondrial oxidative phosphorylation-related genes transcription. Our data showed that autophagy served as a critical mediator of integrating mitochondrial energy metabolism and nuclear transcription. HDAC6 may be a potential target for reducing the survival of HCC cells by interrupting mitochondria-nucleus crosstalk.

scholarly journals Intrinsic Activation of β-catenin Signaling by CRISPR/Cas9-mediated Exon Skipping Contributes to Immune Evasion in Hepatocellular Carcinoma

2021 ◽  
Author(s):  
Masafumi Akasu ◽  
Shu Shimada ◽  
Ayano Kabashima ◽  
Yoshimitsu Akiyama ◽  
Masahiro Shimokawa ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Evasion ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Expression Profiles ◽  
Gene Set Enrichment Analysis ◽  
Clinical Samples ◽  
Engineering System ◽  
Human And Mouse ◽  
Hcc Cells

Abstract Comprehensive analysis of clinical samples has recently identified molecular and immunological classification of hepatocellular carcinoma (HCC), and the CTNNB1 (β-catenin)-mutated subtype exhibits distinctive characteristics of immunosuppressive tumor microenvironment. For clarifying the molecular mechanisms, we first established human and mouse HCC cells with exon 3 skipping of β-catenin, which promoted nuclear translocation and activated the Wnt/β-catenin signaling pathway, by using newly developed multiplex CRISPR/Cas9-based genome engineering system. Gene set enrichment analysis indicated downregulation of immune-associated gene sets in the HCC cells with activated β-catenin signaling. T cell killing assays demonstrated that the mouse Ctnnb1Δex3 HCC cells evaded immune surveillance. Comparative analysis of gene expression profiles between HCC cells harboring wild-type and exon 3 skipping β-catenin elucidated that the expression levels of eight cytokines were commonly decreased in human and mouse β-catenin-mutated HCC cells. Public exome and transcriptome data of 373 human HCC samples showed significant downregulation of five candidate cytokine genes, CCL20, CXCL1, CXCL2, NAMPT and VEGFA, in HCC tumors with β-catenin hotspot mutations. Taken together, this study discovered that cytokine controlled by β-catenin signaling activation could contribute to immune evasion, and provided novel insights into cancer immunotherapy for the β-catenin-mutated HCC subtype.

scholarly journals Intrinsic activation of β-catenin signaling by CRISPR/Cas9-mediated exon skipping contributes to immune evasion in hepatocellular carcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Masafumi Akasu ◽  
Shu Shimada ◽  
Ayano Kabashima ◽  
Yoshimitsu Akiyama ◽  
Masahiro Shimokawa ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Evasion ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Expression Profiles ◽  
Gene Set Enrichment Analysis ◽  
Clinical Samples ◽  
Engineering System ◽  
Human And Mouse ◽  
Hcc Cells

AbstractComprehensive analysis of clinical samples has recently identified molecular and immunological classification of hepatocellular carcinoma (HCC), and the CTNNB1 (β-catenin)-mutated subtype exhibits distinctive characteristics of immunosuppressive tumor microenvironment. For clarifying the molecular mechanisms, we first established human and mouse HCC cells with exon 3 skipping of β-catenin, which promoted nuclear translocation and activated the Wnt/β-catenin signaling pathway, by using newly developed multiplex CRISPR/Cas9-based genome engineering system. Gene set enrichment analysis indicated downregulation of immune-associated gene sets in the HCC cells with activated β-catenin signaling. Comparative analysis of gene expression profiles between HCC cells harboring wild-type and exon 3 skipping β-catenin elucidated that the expression levels of four cytokines were commonly decreased in human and mouse β-catenin-mutated HCC cells. Public exome and transcriptome data of 373 human HCC samples showed significant downregulation of two candidate cytokine genes, CCL20 and CXCL2, in HCC tumors with β-catenin hotspot mutations. T cell killing assays and immunohistochemical analysis of grafted tumor tissues demonstrated that the mouse Ctnnb1Δex3 HCC cells evaded immunosurveillance. Taken together, this study discovered that cytokine controlled by β-catenin signaling activation could contribute to immune evasion, and provided novel insights into cancer immunotherapy for the β-catenin-mutated HCC subtype.

scholarly journals ROS-triggered AMPK de-SUMOylation promotes Warburg effect in hepatocellular carcinoma cells

2020 ◽  
Author(s):  
Shutian Zhang
Keyword(s):  
Oxidative Stress ◽  
Hepatocellular Carcinoma ◽  
Cancer Cells ◽  
Warburg Effect ◽  
Nuclear Translocation ◽  
High Recurrence Rate ◽  
Extracellular Flux ◽  
Mesenchymal Transformation ◽  
Hcc Cells ◽  
The Warburg Effect

AbstractHepatocellular carcinoma (HCC) is the most common malignant tumor of the liver characterized by high recurrence rate and high mortality. The interaction of oxidative stress tolerance and glycometabolism reprogramming in cancer cells results in metastasis and drug resistance in HCC. AMP-activated protein kinase (AMPK) is the master switch of cellular energy metabolism, which regulates the expression of glycolytic rate-limiting enzymes at multiple levels. SUMO Specific Peptidases (SENPs) respond to oxidative stress and modulate AMPK activity. Key scientific issues of this project: Activation of SENP5 by reactive oxygen species (ROS) triggered AMPKα2 de-SUMOylation and cytoplasmic retention to promote the Warburg effect in HCC cells. The human HCC cell lines SMMC-7721 and HepG2 were used in this project. H2O2 (200μM) was used to simulates oxidative stress in HCC cells. Glycolysis flow was monitored by Seahorse XF Extracellular Flux Analyzers. Western blot and immunofluorescence were used to evaluate expression and localization of AMPKα2. Data from TCGA database validated the correlation between SENP5 and glycolysis limiting enzymes. Results: (1) ROS-activated SNEP5 promoted Warburg effect; (2) SENP5 inhibited SUMO2/3 modification and nuclear translocation of AMPKα2; (3) Nuclear localized AMPKα2 activated FOXO3 to inhibit the Warburg effect mediated by c-Myc/Hif-α; (4) ROS activated SENP5 induced sorafenib resistance and epithelial mesenchymal transformation in HCC cells. Conclusion: SENP5 modifies the activation and localization of AMPK to promote glycometabolism reprogramming in HCC. This project provides a new theoretical bases for the treatment of HCC.Graphic abstractROS activation of SENP5 mediates AMPKα2 de-SUMOylation and cytoplasmic retention, which promotes Warburg effect of liver cancer cells

scholarly journals Inhibition of PI3K/Akt signaling suppresses epithelial-to-mesenchymal transition in hepatocellular carcinoma through the Snail/GSK-3/beta-catenin pathway

2020 ◽  
Vol 26 (4) ◽  
pp. 529-539
Author(s):  
Seulki Lee ◽  
Eun Ji Choi ◽  
Eun Ju Cho ◽  
Yun Bin Lee ◽  
Jeong-Hoon Lee ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Epithelial To Mesenchymal Transition ◽  
Nuclear Translocation ◽  
Akt Signaling ◽  
Advanced Hepatocellular Carcinoma ◽  
Beta Catenin ◽  
Mesenchymal Transition ◽  
Pi3k Inhibitors ◽  
Gsk 3Β ◽  
Hcc Cells

Background/Aims: Patients with advanced hepatocellular carcinoma (HCC) have a poor prognosis due to the lack of effective systemic therapies. Epithelial-to-mesenchymal transition (EMT) is a pivotal event in tumor progression, during which cancer cells acquire invasive properties. In this study, we investigated the effects of phosphatidylinositol 3-kinase (PI3K) inhibitors, including LY294002 and idelalisib, on the EMT features of HCC cells in vitro.Methods: Human HCC cell lines, including Huh-BAT and HepG2, were used in this study. Cell proliferation was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide, and cell cycle distributions were evaluated using a flow cytometer by propidium iodide staining. Immunofluorescence staining, quantitative real-time polymerase chain reaction, and immunoblotting were performed to detect EMT-associated changes.Results: PI3K inhibitors suppressed the proliferation and invasion of HCC cells and deregulated the expression of EMT markers, as indicated by increased expression of E-cadherin, an epithelial marker, and decreased expression of N-cadherin, a mesenchymal marker, and Snail, a transcription factor implicated in EMT regulation. Furthermore, LY294002 and idelalisib inhibited the phosphorylation of GSK-3β and induced the nuclear translocation of GSK-3β, which corresponded to the downregulation of Snail and β-catenin expressions in Huh-BAT and HepG2 cells.Conclusions: The inhibition of PI3K/Akt signaling decreases Snail expression by enhancing the nuclear translocation of GSK-3β, which suppresses EMT in HCC cells, suggesting the potential clinical application of PI3K inhibitors for HCC treatment.

Ligustilide counteracts carcinogenesis and hepatocellular carcinoma cell-evoked macrophage M2 polarization by regulating yes-associated protein-mediated interleukin-6 secretion

2021 ◽  
pp. 153537022110104
Author(s):  
Jikang Yang ◽  
Zhiyuan Xing
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Interleukin 6 ◽  
Nuclear Translocation ◽  
Dependent Manner ◽  
Macrophage Recruitment ◽  
Stat3 Signaling ◽  
M2 Polarization ◽  
Hcc Cells

Cross-communication between cancer cells and macrophages within the tumor microenvironment fulfills the critical roles in the progression of cancers, including hepatocellular carcinoma (HCC). Ligustilide exerts anti-inflammation, anti-injury, and anti-tumor pleiotropic pharmacological functions. Nevertheless, its roles in HCC cells and tumor microenvironment remain elusive. In the current study, ligustilide dramatically restrained HCC cell viability and migration but had little cytotoxicity to normal hepatocytes. Importantly, ligustilide antagonized HCC cell co-culture-induced macrophage recruitment and M2 polarization by enhancing the percentage of CD14+CD206+ cells and macrophage M2 markers (CD163, Arg1, CD206, CCL22, IL-10, and TGF-β). Mechanistically, ligustilide repressed yes-associated protein (YAP) activation by reducing nuclear translocation, protein expression, transcriptional regulatory activity of YAP, and increasing p-YAP levels. Noticeably, blocking the YAP offset the suppressive effects of ligustilide on macrophage recruitment and M2 polarization evoked by HCC cells. Moreover, the release of interleukin-6 (IL-6) was mitigated by ligustilide in a YAP-dependent manner in HCC cells, concomitant with inhibition of IL-6R/STAT3 signaling activation. Of interest, interdicting the IL-6 aggravated ligustilide-mediated suppression in HCC-induced macrophage recruitment and M2 polarization; whereas exogenous IL-6 treatment reversed the above effects. Additionally, blockage of IL-6R signaling also overturned IL-6-induced macrophage recruitment and M2 phenotype. Consequently, these findings support a notion that ligustilide not only restrains HCC cell malignancy but also antagonizes HCC cell-evoked macrophage recruitment and M2 polarization by inhibiting YAP/IL-6 release-induced activation of the IL-6 receptor/signal transducer and activator of transcription 3 (IL-6R/STAT3) signaling. Thus, ligustilide may be a promising therapeutic agent to fight HCC by regulating cancer cells and cross-talk between tumor cells and macrophages in tumor microenvironment.

Therapeutic Approaches Using Riboflavin in Mitochondrial Energy Metabolism Disorders

2016 ◽  
Vol 17 (13) ◽  
pp. 1527-1534 ◽  
Author(s):  
Bárbara J. Henriques ◽  
Tânia G. Lucas ◽  
Cláudio M. Gomes
Keyword(s):  
Energy Metabolism ◽  
Therapeutic Approaches ◽  
Mitochondrial Energy Metabolism

scholarly journals Apoptotic Effects of Xanthium strumarium via PI3K/AKT/mTOR Pathway in Hepatocellular Carcinoma

2019 ◽  
Vol 2019 ◽  
pp. 1-13
Author(s):  
Juyoung Kim ◽  
Kyung Hee Jung ◽  
Hyung Won Ryu ◽  
Doo-Young Kim ◽  
Sei-Ryang Oh ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Growth ◽  
Caspase 3 ◽  
Mtor Pathway ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Mechanistic Study ◽  
Migration And Invasion ◽  
Xanthium Strumarium ◽  
Apoptotic Effects ◽  
Hcc Cells

Xanthium strumarium (XS) has been traditionally used as a medicinal herb for treating inflammatory diseases, such as appendicitis, chronic bronchitis, rheumatism, and rhinitis. In this study, we yielded ethanol extracts from XS and investigated whether they could inhibit the progression of hepatocellular carcinoma (HCC) and its underlying mechanism. The XS-5 and XS-6 extracts dose-dependently inhibited the growth and proliferation in HCC cell lines. The apoptotic effects of them were observed via increased levels of cleaved caspase-3 and cleaved PARP, as well as elevated numbers of terminal deoxynucleotidyl transferase-mediated dUTP-biotin end labeling- (TUNEL-) positive apoptotic cells. They also decreased XIAP and Mcl-1 expression via loss of mitochondrial membrane potential. Additionally, they inhibited the invasion and migration of HCC cells. In an ex vivo model, the extracts significantly inhibited tumor cell growth and induced apoptosis by increasing the expression of the cleaved caspase-3. A mechanistic study revealed that they effectively suppressed PI3K/AKT/mTOR signaling pathways in HCC cells. Taken together, our findings demonstrate that they could efficiently not only induce apoptosis but also inhibit cell growth, migration, and invasion of human HCC cells by blocking the PI3K/AKT/mTOR pathway. We suggest XS-5 and XS-6 as novel natural anti-HCC agents.

Mitochondrial energy metabolism is negatively regulated by cannabinoid receptor 1 in intact human epidermis

2020 ◽  
Vol 29 (7) ◽  
pp. 616-622 ◽  
Author(s):  
Attila Oláh ◽  
Majid Alam ◽  
Jérémy Chéret ◽  
Nikolett Gréta Kis ◽  
Zoltán Hegyi ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Cannabinoid Receptor ◽  
Human Epidermis ◽  
Cannabinoid Receptor 1 ◽  
Mitochondrial Energy Metabolism
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