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Arsenic trioxide reverses the chemoresistance in hepatocellular carcinoma: a targeted intervention of 14-3-3?/NF-?B feedback loop.

ABSTRACT: BACKGROUND:Multi-drug resistance (MDR) is one of the main obstacles for treatment of advanced/recurrent hepatocellular carcinoma (HCC). We have previously identified arsenic trioxide (ATO) as an effective metastasis/angiogenesis inhibitor in HCC. Here, we further found that MDR-HCC cells were more sensitive to ATO. METHODS:The MDR-HCC cells were used as experimental models. Biological functions were investigated using cell transfection, polymerase chain reaction, western blot, southwestern blot, immunostaining, immunoprecipitation plus atomic fluorescence spectrometry, and so on. RESULTS:The MDR-HCC cells underwent high oxidative stress condition, and employed adaptive mechanisms for them to survive; while ATO abolished such mechanisms via targeting the 14-3-3?/nuclear factor kappa B (NF-?B) feedback Loop. Briefly, in MDR cells, the increase of ROS activated NF-?B signaling, which transcriptionally activated 14-3-3?. Meanwhile, the activation of NF-?B can be constitutively maintained by 14-3-3?. As a NF-?B inhibitor, ATO transcriptionally inhibited the 14-3-3? mRNA level. Meanwhile, ATO was also validated to directly bind to 14-3-3?, enhancing the degradation of 14-3-3? protein in an ubiquitination-dependent manner. Knockdown of 14-3-3? reduced the ATO-induced reversal extents of drug resistance in MDR cells. CONCLUSION:14-3-3?/NF-?B feedback loop plays an important role in maintaining the MDR phenotype in HCC. Moreover, via targeting such feedback loop, ATO could be considered as a potential molecular targeted agent for the treatment of HCC.

SUBMITTER: Qiu Y

PROVIDER: S-EPMC6302299 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Arsenic trioxide reverses the chemoresistance in hepatocellular carcinoma: a targeted intervention of 14-3-3η/NF-κB feedback loop.

Qiu Yongxin Y Dai Yi Y Zhang Chi C Yang Ye Y Jin Ming M Shan Wenqi W Shen Jian J Lu Ming M Tang Zhaoyang Z Ju Liang L Wang Yuting Y Jiao Ruonan R Xia Yunwei Y Huang Guangming G Yang Lihua L Li Yuan Y Zhang Jianping J Wong Vincent Kam Wai VKW Jiang Zhihong Z

Journal of experimental & clinical cancer research : CR 20181220 1

<h4>Background</h4>Multi-drug resistance (MDR) is one of the main obstacles for treatment of advanced/recurrent hepatocellular carcinoma (HCC). We have previously identified arsenic trioxide (ATO) as an effective metastasis/angiogenesis inhibitor in HCC. Here, we further found that MDR-HCC cells were more sensitive to ATO.<h4>Methods</h4>The MDR-HCC cells were used as experimental models. Biological functions were investigated using cell transfection, polymerase chain reaction, western blot, sou ...[more]

PMID: 30572915

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Project description:ObjectiveArsenic trioxide (Pishuang, Pishi, arsenolite, As2O3, and CAS 1327-53-3), a naturally occurring and toxic mineral as a drug for more than 2000 years in China, has been found to have a valuable function in hepatocellular carcinoma (HCC) in recent years. However, its exact mechanism remains to be elucidated. Therefore, this study was intended to explore the potential anti-HCC mechanism of arsenic trioxide through network pharmacology.MethodsThe potential targets of arsenic trioxide were collected from PubChem and TargetNet. HCC targets were obtained from the GeneCards database. Then, a protein-protein interaction (PPI) network of arsenic trioxide and HCC common targets was established using STRING. GO and KEGG pathway enrichment analyses were performed by the Database for Annotation, Visualization, and Integrated Discovery (DAVID). Finally, an arsenic trioxide-target-pathway-HCC network was built by Cytoscape 3.2.1, and network topological analysis was carried out to screen the key candidate targets.ResultsA total of 346 corresponding targets of arsenic trioxide and 521 HCC-related targets were collected. After target mapping, a total of 52 common targets were obtained. GO analysis showed that the biological process was mainly involved in the negative regulation of cellular senescence, response to tumor necrosis factor, and cellular response to hypoxia. Molecular functions included NF-kappa B binding, enzyme binding, p53 binding, and transcription factor binding. Cellular components mainly were replication fork, ESC/E(Z) complex, RNA polymerase II transcription factor complex, and organelle membrane. KEGG pathways were mainly enriched in the PI3K-Akt signaling pathway, VEGF signaling pathway, p53 signaling pathway, HIF-1 signaling pathway, TNF signaling pathway, AMPK signaling pathway, NF-kappa B signaling pathway, FoxO signaling pathway, ErbB signaling pathway, and MAPK signaling pathway. In the arsenic trioxide-target-pathway-HCC network, targets such as AKT1, RAF1, RELA, TP53, and PTEN had a higher degree. Conclusions. Our study showed that key targets of arsenic trioxide were mainly involved in multiple biological processes and pathways. It provided a theoretical basis for the screening of drug targets.

Dataset Information

Arsenic trioxide reverses the chemoresistance in hepatocellular carcinoma: a targeted intervention of 14-3-3?/NF-?B feedback loop.

Publications

Arsenic trioxide reverses the chemoresistance in hepatocellular carcinoma: a targeted intervention of 14-3-3η/NF-κB feedback loop.

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