Abstract
Tumor cells frequently evolved resistance to cisplatin that greatly compromises the efficacy of chemotherapy. Identification of the mechanisms underlying drug resistance is important for developing new therapeutic approaches. ISG15 is found to be elevated in many human carcinomas and cancer cell lines. Here, we identified that the expressions of ISG15 and ISG15-conjugating system were downregulated in drug resistant A549/DDP cells compared to drug sensitive A549 cells. Silencing of ISG15 robustly elevated the resistance to cisplatin, suggesting ISG15 plays an important role in cisplatin resistance. Quantitative proteomics identified 1296 differentially expressed proteins between the control and ISG15 knockdown cells, showing that ISG15 silencing upregulated proteins in p53 pathway, adherens junction and nucleotide excision repair (NER) pathway. We also found that ISG15 silencing induced cell cycle arrest through stabilizing p53 and increasing HnRNP K expression, which allowed the prolonged time for cells to repair cisplatin-damaged DNA. Taken together, we proved that ISG15 downregulation activated the DNA damage/repair pathway to enhance cisplatin resistance in tumor cells.
Highlights
ISG15, interferon-stimulated gene 15, is the first reported member of the ubiquitin-like protein (UBL) superfamily [1]
We identified that the expressions of ISG15 and ISG15-conjugating system were downregulated in drug resistant A549/DDP cells compared to drug sensitive A549 cells
In the presence of cisplatin, the expressions of ISG15, UBE1L, and UBCH8 were analyzed by western blotting, showing that they were downregulated in A549/ DDP cells (Figure 1B)
Summary
ISG15, interferon-stimulated gene 15, is the first reported member of the ubiquitin-like protein (UBL) superfamily [1]. ISG15 was extensively studied in innate immune response to viral infection [2,3,4] It functions in diverse cellular pathways in the form of ISGylation, an ubiquitin-like modification whereby ISG15 is conjugated to target proteins through a C-terminal diglycine (LRLRGG) motif [5]. ISGylation negatively regulates the ubiquitin-proteasome degradation by directly interfering with polyubiquitination [18]. Elevated expressions of both ISG15 and ISG15conjugating system were found in tumors of different histological origin [19,20,21,22,23,24]. Dysregulated expression of ISG15 was linked to resistance to radiation and chemotherapeutics in tumor cells, suggesting ISG15 was a biomarker for drug sensitivity [27,28,29]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
