Premium
Integrative Analysis of Proteome and Ubiquitylome Reveals Unique Features of Lysosomal and Endocytic Pathways in Gefitinib‐Resistant Non‐Small Cell Lung Cancer Cells
Author(s) -
Li Wang,
Wang Heyong,
Yang Yan,
Zhao Tian,
Zhang Zhixiong,
Tian Ye,
Shi Zhaomie,
Peng Xiaojun,
Li Fei,
Feng Yonghong,
Zhang Lei,
Jiang Gening,
Zhang Fan
Publication year - 2018
Publication title -
proteomics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.26
H-Index - 167
eISSN - 1615-9861
pISSN - 1615-9853
DOI - 10.1002/pmic.201700388
Subject(s) - gefitinib , endocytic cycle , biology , downregulation and upregulation , cancer research , autophagy , ubiquitin , microbiology and biotechnology , gene knockdown , signal transduction , immunoprecipitation , epidermal growth factor receptor , cell , cancer , cell culture , biochemistry , endocytosis , apoptosis , genetics , gene
Non‐small cell lung cancer (NSCLC) patients carrying EGFR activating mutations treated with gefitinib, a tyrosine kinase inhibitor, will develop drug resistance. Ubiquitylation is one of major posttranslational modifications of proteins affecting the stability or function of proteins. However, the role of protein ubiquitylation in gefitinib resistance is poorly understood. To systematically identify the global change in protein expression and ubiquitylation during gefitinib resistance, a quantitative global proteome and ubiquitylome study in a pair of gefitinib‐resistant and sensitive NSCLC cells is carried out. Altogether, changes in expression of 3773 proteins are quantified, and changes in ubiquitylation of 2893 lysine sites in 1415 proteins are measured in both cells. Interestingly, lysosomal and endocytic pathways, which are involved in autophagy regulation, are enriched with upregulated proteins or ubiquitylated proteins in gefitinib‐resistant cells. In addition, HMGA2 overexpression or ALOX5 knockdown suppresses gefitinib resistance in NSCLC cells by inhibiting autophagy. Overall, these results reveal the previously unknown global ubiquitylome and proteomic features associated with gefitinib resistance, uncover the opposing roles of HMGA2 or ALOX5 in regulating gefitinib resistance and autophagy, and will help to identify new therapeutic targets in overcoming gefitinib resistance.