https://scholars.lib.ntu.edu.tw/handle/123456789/522058
標題: | Quantitative phosphoproteomic analysis identifies the potential therapeutic target EphA2 for overcoming sorafenib resistance in hepatocellular carcinoma cells | 作者: | Chen, Chih-Ta Liao, Li-Zhu Lu, Ching-Hui Huang, Yung-Hsuan Lin, Yu-Kie Lin, Jung-Hsin LU-PING CHOW |
公開日期: | 2020 | 出版社: | NATURE PUBLISHING GROUP | 卷: | 52 | 期: | 3 | 起(迄)頁: | 497 | 來源出版物: | Experimental & molecular medicine | 摘要: | Limited therapeutic options are available for advanced-stage hepatocellular carcinoma owing to its poor diagnosis. Drug resistance to sorafenib, the only available targeted agent, is commonly reported. The comprehensive elucidation of the mechanisms underlying sorafenib resistance may thus aid in the development of more efficacious therapeutic agents. To clarify the signaling changes contributing to resistance, we applied quantitative phosphoproteomics to analyze the differential phosphorylation changes between parental and sorafenib-resistant HuH-7 cells. Consequently, an average of ~1500 differential phosphoproteins were identified and quantified, among which 533 were significantly upregulated in resistant cells. Further bioinformatic integration via functional categorization annotation, pathway enrichment and interaction linkage analysis led to the discovery of alterations in pathways associated with cell adhesion and motility, cell survival and cell growth and the identification of a novel target, EphA2, in resistant HuH-7R cells. In vitro functional analysis indicated that the suppression of EphA2 function impairs cell proliferation and motility and, most importantly, overcomes sorafenib resistance. The attenuation of sorafenib resistance may be achieved prior to its development through the modulation of EphA2 and the subsequent inhibition of Akt activity. Binding analyses and in silico modeling revealed a ligand mimic lead compound, prazosin, that could abate the ligand-independent oncogenic activity of EphA2. Finally, data obtained from in vivo animal models verified that the simultaneous inhibition of EphA2 with sorafenib treatment can effectively overcome sorafenib resistance and extend the projected survival of resistant tumor-bearing mice. Thus our findings regarding the targeting of EphA2 may provide an effective approach for overcoming sorafenib resistance and may contribute to the management of advanced hepatocellular carcinoma. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/522058 | ISSN: | 1226-3613 | DOI: | 10.1038/s12276-020-0404-2 | SDG/關鍵字: | 2 [[2 (2,6 dimethoxyphenoxy)ethyl]aminomethyl] 1,4 benzodioxan; bunazosin; clozapine; cyproheptadine; doxazosin; ephrin receptor A2; ketanserin; phentolamine; phosphoprotein; prazosin; protein kinase B; sorafenib; tamsulosin; terazosin; EPHA2 protein, human; ephrin receptor A2; phosphoprotein; sorafenib; animal experiment; animal model; animal tissue; Article; bioinformatics; cancer resistance; cell adhesion; cell growth; cell motility; cell proliferation; cell survival; computer model; controlled study; drug potentiation; drug resistance; drug screening; drug targeting; embryo; enzyme inhibition; functional categorization annotation; Huh-7 cell line; human; human cell; IC50; in vitro study; in vivo study; interaction linkage analysis; liver cell carcinoma; mouse; mouse model; nonhuman; pathway enrichment; phosphoproteomic analysis; protein analysis; protein binding; protein function; protein phosphorylation; proteomics; quantitative analysis; tumor xenograft; upregulation; animal; cell motion; disease model; drug resistance; genetics; liver tumor; procedures; proteomics; signal transduction; tumor cell line; Animals; Carcinoma, Hepatocellular; Cell Adhesion; Cell Line, Tumor; Cell Movement; Cell Proliferation; Disease Models, Animal; Drug Resistance, Neoplasm; Humans; Liver Neoplasms; Mice; Phosphoproteins; Proteomics; Receptor, EphA2; Signal Transduction; Sorafenib; Xenograft Model Antitumor Assays |
顯示於: | 生物化學暨分子生物學科研究所 |
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