Integrated Analysis of Global Proteome and Phosphoproteome in Cisplatin Resistant Bladder Cancer Cell Revealed the Molecular Signature Predictive to Patient Survival

ABSTRACT: Cisplatin-based chemotherapy is the standard care regimen in bladder cancer (BC). However, resistance to the therapy whose molecular mechanisms of the resistance are not fully elucidated rapidly develops in BC patients. Here we introduced multidimensional proteomic analysis providing different levels of protein information, which included global proteome and phosphorpoteome perturbed by EGF using the cisplatin resistant BC model. Integrated analysis of protein expression and phosphorylation provided comprehensive profiles of altered proteins in cisplatin resistant cells that are dependent and independent on EGF, as well as suggesting significance of protein phosphorylation in resistance mechanisms in BC. From the reconstruction of cisplatin resistance associated network model and subsequent kinase enrichment analysis, we have identified three key kinases, CDK2, CHEK1, and ERBB2 as central regulators mediating cisplatin resistance. Experimental validation showed phosphorylation events in these central kinases and their putative substrates, suggesting evidence that activation of three kinases are important to acquired resistance to cisplatin in BC. Expanded analysis with this proteomic discovery to transcriptome profiles from BC cohorts nominated the 7 gene panel associated with poor survival after cisplatin-based chemotherapy. These findings provide insightful strategies to classify high-risk BC patients upon current chemotherapies and to identify therapeutic targets for recurrence disease.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

DISEASE(S): Bladder Adenocarcinoma

SUBMITTER: Jae Hun Jung  

LAB HEAD: Kwang Pyo Kim

PROVIDER: PXD005308 | Pride | 2020-05-26

REPOSITORIES: Pride