scholarly journals Autophagy-related Gene 7 (ATG7) and Reactive Oxygen Species/Extracellular Signal-regulated Kinase Regulate Tetrandrine-induced Autophagy in Human Hepatocellular Carcinoma

2012 ◽  
Vol 287 (42) ◽  
pp. 35576-35588 ◽  
Author(s):  
Ke Gong ◽  
Chao Chen ◽  
Yao Zhan ◽  
Yan Chen ◽  
Zebo Huang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Reactive Oxygen Species ◽  
Chemotherapeutic Agent ◽  
Reactive Oxygen ◽  
Human Hepatocellular Carcinoma ◽  
Dependent Manner ◽  
Oxygen Species ◽  
Related Gene ◽  
Antitumor Effects ◽  
Hcc Cells

Tetrandrine, a bisbenzylisoquinoline alkaloid isolated from the broadly used Chinese medicinal herb Stephaniae tetrandrae, exhibits potent antitumor effects and has the potential to be used as a cancer chemotherapeutic agent. We previously reported that high concentrations of tetrandrine induce apoptosis in liver cancer cells. Here, we found that in human hepatocellular carcinoma (HCC) cells, a low dose of tetrandrine (5 μm) induced the expression of LC3-II, resulted in the formation of acidic autophagolysosome vacuoles (AVOs), and caused a punctate fluorescence pattern with the GFP-LC3 protein, which all are markers for cellular autophagy. Tetrandrine induced the production of intracellular reactive oxygen species (ROS), and treatment with ROS scavengers significantly abrogated the tetrandrine-induced autophagy. These results suggest that the generation of ROS plays an important role in promoting tetrandrine-induced autophagy. Tetrandrine-induced mitochondrial dysfunction resulted in ROS accumulation and autophagy. ROS generation activated the ERK MAP kinase, and the ERK signaling pathway at least partially contributed to tetrandrine-induced autophagy in HCC cells. Moreover, we found that tetrandrine transcriptionally regulated the expression of autophagy related gene 7 (ATG7), which promoted tetrandrine-induced autophagy. In addition to in vitro studies, similar results were also observed in vivo, where tetrandrine caused the accumulation of ROS and induced cell autophagy in a tumor xenograft model. Interestingly, tetrandrine treatment also induced autophagy in a ROS-dependent manner in C. elegans muscle cells. Therefore, these findings suggest that tetrandrine is a potent autophagy agonist and may be a promising clinical chemotherapeutic agent.

scholarly journals Reactive Oxygen Species-Mediated Cezanne Inactivation by Oxidation of its Catalytic Cysteine Residue in Hepatocellular Carcinoma

2019 ◽  
Vol 27 (9) ◽  
pp. 1069-1077
Author(s):  
Zhongyuan Yin ◽  
Lin Yang ◽  
Feng Wu ◽  
Jinshuo Fan ◽  
Juanjuan Xu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Reactive Oxygen Species ◽  
Reactive Oxygen ◽  
Matrix Metalloproteinase 2 ◽  
Intercellular Adhesion Molecule ◽  
Oxygen Species ◽  
Cysteine Oxidation ◽  
Diphenylene Iodonium ◽  
Hcc Cells ◽  
Inflammatory Effect

Cysteine oxidation occurs at the active site of deubiquitinases (DUBs) during many biologic signaling cascades. Here we report that hepatocellular carcinoma cells (HCCs) generated higher levels of endogenous reactive oxygen species (ROS). This elevated ROS production was inhibited by NADPH oxidase inhibitor diphenylene iodonium (DPI) and mitochondria electron chain inhibitor rotenone in HCC cells. Moreover, we found that H2O2 could activate NF-κB-dependent inflammatory effect through increased induction of matrix metalloproteinase 2 (MMP2), MMP9, and intercellular adhesion molecule 1 (ICAM1) expression levels. In addition, we found that H2O2 could prolong NF-κB activation by suppressing the negative regulatory functions of Cezanne in HCC cells. Ubiquitin-derived thiol-reactive probe (HA-UbVME) assay and biotin-tagged 1,3-cyclohexadione derivative (DCP-Bio1) assay showed that H2O2 has the capacity to inhibit the catalytic activity of Cezanne, and the reducing agent, DTT, could reactivate the Cezanne deubiquitinating enzyme activity. Taken all together, these findings demonstrated an important role for oxidation of Cezanne by ROS in regulation of the inflammatory effect of hepatocellular carcinoma.

scholarly journals Ivalin Induces Mitochondria-Mediated Apoptosis Associated with the NF-κB Activation in Human Hepatocellular Carcinoma SMMC-7721 Cells

Molecules ◽  
2019 ◽  
Vol 24 (20) ◽  
pp. 3809
Author(s):  
Zhuo Han ◽  
Fang-yuan Liu ◽  
Shi-qi Lin ◽  
Cai-yun Zhang ◽  
Jia-hui Ma ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Reactive Oxygen Species ◽  
Reactive Oxygen Species Generation ◽  
Reactive Oxygen ◽  
Mitochondrial Pathway ◽  
Human Hepatocellular Carcinoma ◽  
Induction Effect ◽  
Oxygen Species ◽  
Microtubule Depolymerization ◽  
Apoptotic Effect

Ivalin, a natural compound isolated from Carpesium divaricatum, showed excellent microtubule depolymerization activities among human hepatocellular carcinoma in our previous work. Here, we investigated its functions on mitochondria-mediated apoptosis in hepatocellular carcinoma SMMC-7721 cells. DAPI (4′,6-diamidino-2-phenylindole) staining, annexin V-fluorexcein isothiocyanate (FITC) apoptosis detection, and western blotting were applied to explore the apoptotic effect of Ivalin. Next, the induction effect of Ivalin on the mitochondrial pathway was also confirmed via a series of phenomena including the damage of mitochondria membrane potential, mitochondria cytochrome c escape, cleaved caspase-3 induction, and the reactive oxygen species generation. In this connection, we understood that Ivalin induced apoptosis through the mitochondrial pathway and the overload of reactive oxygen species. Furthermore, we found that the activation of nuclear factor-κB (NF-κB) and subsequent p53 induction were associated with the apoptotic effect of Ivalin. These data confirmed that Ivalin might be a promising pro-apoptotic compound that can be utilized as a potential drug for clinical treatment.

scholarly journals Glutathione S-transferase A2 (GSTA2) Promotes Hepatocellular Carcinoma Recurrence After Liver Transplantation Through Modulating Reactive Oxygen Species Metabolism

2020 ◽  
Author(s):  
Kevin Tak-Pan NG ◽  
Oscar Wai-Ho Yeung ◽  
Yin Fan Lam ◽  
Jiang Liu ◽  
Hui Liu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Reactive Oxygen Species ◽  
Liver Transplantation ◽  
Early Phase ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Glutathione S Transferase ◽  
Proliferation And Metastasis ◽  
Hcc Recurrence ◽  
Hcc Cells

Abstract BackgroundAn inevitable hepatic injury at the early phase after liver transplantation vitally affects the late phase hepatocellular carcinoma (HCC) recurrence. However, their linkage and underlying risk factors of HCC recurrence are unclear. This study aimed to clarify the clinical impact and functional roles of glutathione S-transferase A2 (GSTA2) in affecting HCC recurrence after liver transplantation.MethodsExpression significance and prognostic value of hepatic and circulating GSTA2 in HCC recipients were examined. The polymorphism of GSTA2 transcript was analysed by Sanger sequencing. The functions and molecular mechanisms of GSTA2 in the proliferation and metastasis of HCC were characterized by molecular, cellular and animal experiments. ResultsThe GSTA2 expression was significantly correlated with the early phase hepatic and systemic injury and reactive oxygen species (ROS) level after liver transplantation. Importantly, the level of the early phase circulating GSTA2 protein was a significant predictor of HCC recurrence and survival of HCC recipients. Heterogeneous single nucleotide polymorphism at G335C of GSTA2 was significantly associated with poor survival of HCC recipients. The GSTA2 expression was positively correlated with the aggressiveness of HCCs. Overexpression of GSTA2, by endogenous or exogenous approaches, could enhance the proliferation and invasion of HCCs through activating epithelial-mesenchymal-transition promoting proteins. Targeted inhibition of GSTA2 remarkably suppressed the proliferation and metastasis of HCCs. Increased level of GSTA2 could compensate the H2O2-induced ROS stress and therefore protect the HCC cells from damage. Alteration of GSTA2 expression in HCC cells could influence the activation of ROS-associated JNK and AKT signaling pathways and the expression of ROS-associated genes in responding to the H2O2 condition. ConclusionsOur research discovered GSTA2 to be the significant risk factor of HCC recurrence via providing a favorable ROS environment for HCC to survival and progress. This study presents a novel functional biomarker for combating HCC recurrence after liver transplantation.

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