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Updated: Feb 16, 2026
Purification of Ubiquitinated p53 Proteins from Mammalian Cells
Published on: March 21, 2022
ISG15 silencing increases cisplatin resistance via activating p53-mediated cell DNA repair
Yi Huo1, Zhaoyun Zong1, Qingtao Wang2
1MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing, China.
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.
Insights
Interferon-stimulated gene 15 (ISG15) downregulation enhances tumor cell resistance to cisplatin chemotherapy. Silencing ISG15 activates DNA repair pathways, promoting survival against chemotherapy drugs.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Cisplatin chemotherapy efficacy is often compromised by acquired tumor cell resistance.
- Understanding drug resistance mechanisms is crucial for developing effective cancer therapies.
- Interferon-stimulated gene 15 (ISG15) is upregulated in various human carcinomas.
Purpose of the Study:
- To investigate the role of ISG15 in cisplatin resistance in lung cancer cells.
- To elucidate the molecular mechanisms by which ISG15 influences chemotherapy response.
Main Methods:
- Comparison of ISG15 expression in cisplatin-sensitive (A549) versus resistant (A549/DDP) cells.
- ISG15 knockdown experiments to assess its impact on cisplatin resistance.
- Quantitative proteomics to identify differentially expressed proteins upon ISG15 silencing.
- Analysis of cell cycle progression and DNA repair pathway activation.
Main Results:
- ISG15 and its conjugating system were downregulated in cisplatin-resistant A549/DDP cells.
- ISG15 silencing significantly increased resistance to cisplatin.
- Proteomic analysis revealed ISG15 knockdown upregulated proteins in the p53, adherens junction, and nucleotide excision repair (NER) pathways.
- ISG15 silencing induced cell cycle arrest by stabilizing p53 and increasing HnRNP K, enhancing DNA repair.
Conclusions:
- ISG15 downregulation is a mechanism contributing to cisplatin resistance in tumor cells.
- Reduced ISG15 activates DNA damage/repair pathways, promoting cell survival during chemotherapy.
- Targeting ISG15 or related pathways may offer novel therapeutic strategies against cisplatin resistance.
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