The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
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Involvement of adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1 in diallyl trisulfide-induced cytotoxicity in hepatocellular carcinoma cells

  • Guan, Feng (Department of Pathology, Renmin Hospital of Wuhan University) ;
  • Ding, Youming (Department of Hepatobiliary & Laparascopic Surgery, Renmin Hospital of Wuhan University) ;
  • He, Yikang (Tongji Medical College Huazhong University of Science and Technology, School of Nursing) ;
  • Li, Lu (Department of Pathology and Pathophysiology, Wuhan University Taikang Medical School (School of Basic Medical Sciences)) ;
  • Yang, Xinyu (Department of Pathology and Pathophysiology, Wuhan University Taikang Medical School (School of Basic Medical Sciences)) ;
  • Wang, Changhua (Department of Pathology and Pathophysiology, Wuhan University Taikang Medical School (School of Basic Medical Sciences)) ;
  • Hu, Mingbai (Department of Breast and Thyroid Surgery, Zhongnan Hospital of Wuhan University)
  • Received : 2022.03.23
  • Accepted : 2022.07.27
  • Published : 2022.11.01
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Abstract

It has been demonstrated that APPL1 (adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1) is involved in the regulation of several growth-related signaling pathways and thus closely associated with the development and progression of some cancers. Diallyl trisulfide (DAT), a garlic-derived bioactive compound, exerts selective cytotoxicity to various human cancer cells through interfering with pro-survival signaling pathways. However, whether and how DAT affects survival of human hepatocellular carcinoma (HCC) cells remain unclear. Herein, we tested the hypothesis of the involvement of APPL1 in DAT-induced cytotoxicity in HCC HepG2 cells. We found that Lys 63 (K63)-linked polyubiquitination of APPL1 was significantly decreased whereas phosphorylation of APPL1 at serine residues remained unchanged in DAT-treated HepG2 cells. Compared with wild-type APPL1, overexpression of APPL1 K63R mutant dramatically increased cell apoptosis and mitigated cell survival, along with a reduction of phosphorylation of STAT3, Akt, and Erk1/2. In addition, DAT administration markedly reduced protein levels of intracellular TNF receptor-associated factor 6 (TRAF6). Genetic inhibition of TRAF6 decreased K63-linked polyubiquitination of APPL1. Moreover, the cytotoxicity impacts of DAT on HepG2 cells were greatly attenuated by overexpression of wild-type APPL1. Taken together, these results suggest that APPL1 polyubiquitination probably mediates the inhibitory effects of DAT on survival of HepG2 cells by modulating STAT3, Akt, and Erk1/2 pathways.

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References

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