期刊
CANCER LETTERS
卷 437, 期 -, 页码 1-12出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2018.08.014
关键词
Global proteome; Phosphoproteomics; Cisplatin resistance; Bladder cancer; Biological network; Competing interests
类别
资金
- Bio and Medical Technology Development Program though National Research Foundation of Korea - Korean Ministry of Education, Science and Technology [2012M3A9B6055305]
- Multiomics Research Program [NRF-2012M3AB9036675]
- Korean Ministry of Science, ICT, and Future Planning
- National Institutes of Health [1U01DK103260, 1R01DK100974, U24 DK097154]
- National Institutes of Health (NIH NCATS UCLA CTSI) [UL1TR000124]
- Department of Defense [W81XWH-15-1-0415]
- Centers for Disease Controls and Prevention [1U01DP006079]
- IMAGINE NO IC Research Grant
- Steven Spielberg Discovery Fund in Prostate Cancer Research Career Development Awards
- U.S.-Egypt Science and Technology Joint Fund
- Interstitial Cystitis Association Pilot Grant
- Fishbein Family IC Research Grant
- New York Academy of Medicine
- Boston Children's Hospital Faculty Development
- National Academy of Sciences, Engineering, and Medicine (NAS)
- United States Agency for International Development
Background: Cisplatin-based chemotherapy is currently part of the standard of care for bladder cancer (BC). Unfortunately, some patients respond poorly to chemotherapy and have acquired or developed resistance. The molecular mechanisms underlying this resistance remain unclear. Here, we introduce a multidimensional proteomic analysis of a cisplatin-resistant BC model that provides different levels of protein information, including that of the global proteome and phosphoproteome. Methods: To characterize the global proteome and phosphoproteome in cisplatin-resistant BC cells, liquid chromatography-mass spectrometry/mass spectrometry experiments combined with comprehensive bioinformatics analysis were performed. Perturbed expression and phosphorylation levels of key kinases associated with cisplatin resistance were further studied using various cell biology assays, including western blot analysis. Results: Analyses of protein expression and phosphorylation identified significantly altered proteins, which were also EGF-dependent and independent. This suggests that protein phosphorylation plays a significant role in cisplatin-resistant BC. Additional network analysis of significantly altered proteins revealed CDK2, CHEK1, and ERBB2 as central regulators mediating cisplatin resistance. In addition to this, we identified the CDK2 network, which consists of CDK2 and its 5 substrates, as being significantly associated with poor survival after cisplatin chemotherapy. Conclusions: Collectively, these findings potentially provide a novel way of classifying higher-risk patients and may guide future research in developing therapeutic targets.
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