Arsenic trioxide reverses the chemoresistance in hepatocellular carcinoma: a targeted intervention of 14–3-3η/NF-κB feedback loop
| Autor: | Yi Dai, Yunwei Xia, Ye Yang, Jian Shen, Lihua Yang, Yuan Li, Zhi-Hong Jiang, Vincent Kam Wai Wong, Chi Zhang, Yuting Wang, Liang Ju, Guangming Huang, Ming Lu, Wenqi Shan, Ruonan Jiao, Qiu Yongxin, Jianping Zhang, Ming Jin, Zhaoyang Tang |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Carcinoma Hepatocellular Hepatocellular carcinoma Immunoprecipitation Transfection lcsh:RC254-282 Nuclear factor kappa B 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Arsenic Trioxide Western blot Cell Line Tumor 14–3-3η medicine Humans Arsenic trioxide Feedback Physiological Gene knockdown medicine.diagnostic_test Chemistry Research Liver Neoplasms NF-kappa B NF-κB lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Angiogenesis inhibitor Multi-drug resistance 030104 developmental biology 14-3-3 Proteins Oncology Drug Resistance Neoplasm Apoptosis 030220 oncology & carcinogenesis Cancer research Signal Transduction |
| Zdroj: | Journal of Experimental & Clinical Cancer Research : CR Journal of Experimental & Clinical Cancer Research, Vol 37, Iss 1, Pp 1-11 (2018) |
| ISSN: | 1756-9966 |
| DOI: | 10.1186/s13046-018-1005-y |
| Popis: | 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 14–3-3η/nuclear factor kappa B (NF-κB) feedback Loop. Briefly, in MDR cells, the increase of ROS activated NF-κB signaling, which transcriptionally activated 14–3-3η. Meanwhile, the activation of NF-κB can be constitutively maintained by 14–3-3η. As a NF-κB inhibitor, ATO transcriptionally inhibited the 14–3-3η mRNA level. Meanwhile, ATO was also validated to directly bind to 14–3-3η, enhancing the degradation of 14–3-3η protein in an ubiquitination-dependent manner. Knockdown of 14–3-3η reduced the ATO-induced reversal extents of drug resistance in MDR cells. Conclusion 14–3-3η/NF-κB 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. Electronic supplementary material The online version of this article (10.1186/s13046-018-1005-y) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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