Proteomics Analysis Of Cisplatin Resistance In Cancer Cells

Cisplatin and other platinum drugs are widely used in the treatment of solid tumors.The early response to cisplatin treatment is commendable,but most patients relapsed and gained resistance to cisplatin after the treatment,which greatly comprimises the drug effecacy.In order to find new therapeutic targets and improve the therapeutic outcome of cisplatin,it is urgent to have a deeper understanding to the mechanisms of cisplatin resistance.In the present study,we established the molecular network of cisplatin resistance based on the differentially expressed proteins between A2780 and its cisplatin resistant cells A2780-DR identified by quantative proteomics analysis.We proved that Rab 5C and Rab 11 B mediated endocytosis and anti-oxidant system including GSH were involved in the cisplatin resistance and glycolysis was downregulated in A2780-DR cells.Vimentin expression was reduced in cisplatin resistant cells and we proved that vimentin regulated cisplatin resistance.Proteomics analysis of vimentin silencing cells and the control cellsclarify provided the mechanism of vimentin mediated cisplatin resistance:upregulation of exocytotic proteins CHMP2 B and PDZK1 in vimentin silencing cells contributed to the decreased cisplatin accumulation;silencing of vimentin induced cells to acquire stem cell-like phenotype;and vimentin silencing increased the retention of Cdc25 C in the cytoplasm,leading to the inactivation of Cdk1 and G2 phase arrest that prolonged the time for cisplatin-damaged DNA repair.Furthermore,cisplatin treatment increased the expression of ISG15 while the expression of ISG15 was markedly downregulated in cisplatin resistant cells A549/DDP as compared to the control cells.ISG15 silencing robustly elevated the resistance to cisplatin.Based on the differentially expressed proteins identified by quantitative proteomics analysis between ISG15 silencing cells and control cells,we elucidated the mechanism of ISG15 mediated cisplatin resistance: ISG15 silencing upregulated both p53 and HnRNP K,leading to the activatioin of p53 pathway which was followed by the decreased apoptosis and cell cycle arrest while it upregualted PCNA and other proteins involving in DNA repair.In conclusion,using proteomics analysis,we established the molecular network of cisplatin resistance and provided the mechanistic information on vimentin-mediated and ISG15-mediated cisplatin resistance...