Integrated proteomic and phosphoproteomic analyses of cisplatin-sensitive and resistant bladder cancer cells reveal CDK2 network as a key therapeutic target

Details

• Alternative Title:
  Cancer Lett
• Personal Author:
  Jung, Jae Hun ; You, Sungyong ; Oh, Jae Won ; Yoon, Junhee ; Yeon, Austin ; Shahid, Muhammad ; Cho, Eunho ; Sairam, Vikram ; Park, Taeeun D. ; Kim, Kwang Pyo ; Kim, Jayoung
• Description:
  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.
  
  
• Subjects:
  Aged Antineoplastic Agents Article Biological Network Bladder Cancer Cell Line, Tumor Cisplatin Cisplatin Resistance Cyclin-Dependent Kinase 2 Drug Resistance, Neoplasm Female Global Proteome Humans Kaplan-Meier Estimate Male Middle Aged Phosphoproteins Phosphoproteomics Phosphorylation Protein Interaction Maps Proteome Proteomics Urinary Bladder Neoplasms

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• Source:
  Cancer Lett. 437:1-12
• Pubmed ID:
  30145203
• Pubmed Central ID:
  PMC6181132
• Document Type:
  Journal Article
• Funding:
  U01DP006079/ACL HHS/United States ; UL1 TR000124/TR/NCATS NIH HHS/United States ; U24 DK097154/DK/NIDDK NIH HHS/United States ; U01 DP006079/DP/NCCDPHP CDC HHS/United States ; R01 DK100974/DK/NIDDK NIH HHS/United States ; U01 DK103260/DK/NIDDK NIH HHS/United States
• Volume:
  437
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:ba7b6160b5545776956303d6158759fb7511add0fada7c80bbd8e077a8e34c75
• Download URL:
  https://stacks.cdc.gov/view/cdc/59722/cdc_59722_DS1.pdf
• File Type:
  [PDF - 2.91 MB ]