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

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

  • J Exp Clin Cancer Res. 2018 Dec 20;37(1):321. doi: 10.1186/s13046-018-1005-y.
Yongxin Qiu 1,  Yi Dai 2 3,  Chi Zhang 1,  Ye Yang 2,  Ming Jin 2,  Wenqi Shan 2,  Jian Shen 1,  Ming Lu 1,  Zhaoyang Tang 1,  Liang Ju 1,  Yuting Wang 2,  Ruonan Jiao 2,  Yunwei Xia 2,  Guangming Huang 1,  Lihua Yang 1,  Yuan Li 4 5,  Jianping Zhang 6,  Vincent Kam Wai Wong 7,  Zhihong Jiang 8
Affiliations

Affiliations

  • 1 The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.
  • 2 Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center For Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China.
  • 3 State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, China.
  • 4 Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center For Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China. liyuan@njmu.edu.cn.
  • 5 State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, China. liyuan@njmu.edu.cn.
  • 6 The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China. zjpnjmu@aliyun.com.
  • 7 State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, China. kawwong@must.edu.mo.
  • 8 State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, China. zhjiang@must.edu.mo.
PMID: 30572915 DOI: 10.1186/s13046-018-1005-y
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 14-3-3η/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.

Keywords

14–3-3η; Arsenic trioxide; Hepatocellular carcinoma; Multi-drug resistance; Nuclear factor kappa B.

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