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Original Article

Korean J Physiol Pharmacol 2022; 26(6): 457-468

Published online November 1, 2022 https://doi.org/10.4196/kjpp.2022.26.6.457

Copyright © Korean J Physiol Pharmacol.

Involvement of adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1 in diallyl trisulfide-induced cytotoxicity in hepatocellular carcinoma cells

Feng Guan1,#, Youming Ding2,#, Yikang He3, Lu Li4, Xinyu Yang4, Changhua Wang4,*, and Mingbai Hu5,*

1Department of Pathology, Renmin Hospital of Wuhan University, 2Department of Hepatobiliary & Laparascopic Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, 3Tongji Medical College Huazhong University of Science and Technology, School of Nursing, Wuhan 430030, 4Department of Pathology and Pathophysiology, Wuhan University Taikang Medical School (School of Basic Medical Sciences), 5Department of Breast and Thyroid Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China

Correspondence to:Changhua Wang
E-mail: chwang0525@whu.edu.cn
Mingbai Hu
E-mail: humingbai@126.com

#These authors contributed equally to this work.

Author contributions: F.G., Y.D., Y.H., L.L., and X.Y. performed the experiments, interpreted and analyzed data, and conducted statistical analyses. M.H. and C.W. designed and supervised the project, and wrote the manuscript. All authors read and approved submission of the manuscript. Y.H. is an undergraduate student working in the laboratory.

Received: March 23, 2022; Revised: July 14, 2022; Accepted: July 27, 2022

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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.

Keywords: APPL1, Cell survival, Diallyl trisulfide, Hepatocellular carcinoma cells

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