M M Carey, T R O'Donovan, C M Coveney, S L McKenna
{"title":"IFN-α存在下抑制USP18可提高食管癌细胞系的凋亡、自噬和化学敏感性。","authors":"M M Carey, T R O'Donovan, C M Coveney, S L McKenna","doi":"10.1016/j.yexcr.2025.114768","DOIUrl":null,"url":null,"abstract":"<p><p>Oesophageal cancer remains a poor-prognosis disease with a five-year survival of 20 %. Chemoresistance poses a significant challenge, and its mechanisms remain unclear. Our previous study found that the ISGylation network is differentially expressed in drug-sensitive and resistant oesophageal cancer cells. ISGylation involves conjugating Interferon-Stimulated Gene 15 (ISG15) to target proteins, regulated by E1, E2, and E3 enzymes, similar to ubiquitin. Ubiquitin Specific Peptidase 18 (USP18) removes ISG15 and negatively regulates the type I interferon (IFN) response. We investigated whether USP18 expression influences the chemosensitivity of two resistant oesophageal cancer cell lines. Treatment with IFN-α ( ± 5-fluorouracil (5-FU) or oxaliplatin) induces ISGylation network proteins, including USP18. ISG15 conjugation is only detected after USP18 depletion with siRNA. Silencing USP18 significantly increased sensitivity to 5-FU and oxaliplatin, inducing extensive apoptosis in both cell lines previously regarded as apoptosis incompetent. USP18 depletion also elevated LC3 II expression and autophagosome formation induced by IFN-α ( ± chemotherapeutic agents), indicative of autophagy. These findings demonstrate that strategies to inhibit USP18 could re-engage cell death signalling and restore sensitivity to chemo-resistant oesophageal cancer cells.</p>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":" ","pages":"114768"},"PeriodicalIF":3.5000,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Inhibition of USP18 in the presence of IFN-α elevates apoptosis, autophagy, and chemosensitivity of oesophageal cancer cell lines.\",\"authors\":\"M M Carey, T R O'Donovan, C M Coveney, S L McKenna\",\"doi\":\"10.1016/j.yexcr.2025.114768\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Oesophageal cancer remains a poor-prognosis disease with a five-year survival of 20 %. Chemoresistance poses a significant challenge, and its mechanisms remain unclear. Our previous study found that the ISGylation network is differentially expressed in drug-sensitive and resistant oesophageal cancer cells. ISGylation involves conjugating Interferon-Stimulated Gene 15 (ISG15) to target proteins, regulated by E1, E2, and E3 enzymes, similar to ubiquitin. Ubiquitin Specific Peptidase 18 (USP18) removes ISG15 and negatively regulates the type I interferon (IFN) response. We investigated whether USP18 expression influences the chemosensitivity of two resistant oesophageal cancer cell lines. Treatment with IFN-α ( ± 5-fluorouracil (5-FU) or oxaliplatin) induces ISGylation network proteins, including USP18. ISG15 conjugation is only detected after USP18 depletion with siRNA. Silencing USP18 significantly increased sensitivity to 5-FU and oxaliplatin, inducing extensive apoptosis in both cell lines previously regarded as apoptosis incompetent. USP18 depletion also elevated LC3 II expression and autophagosome formation induced by IFN-α ( ± chemotherapeutic agents), indicative of autophagy. These findings demonstrate that strategies to inhibit USP18 could re-engage cell death signalling and restore sensitivity to chemo-resistant oesophageal cancer cells.</p>\",\"PeriodicalId\":12227,\"journal\":{\"name\":\"Experimental cell research\",\"volume\":\" \",\"pages\":\"114768\"},\"PeriodicalIF\":3.5000,\"publicationDate\":\"2025-09-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Experimental cell research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.yexcr.2025.114768\",\"RegionNum\":3,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Experimental cell research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.yexcr.2025.114768","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
Inhibition of USP18 in the presence of IFN-α elevates apoptosis, autophagy, and chemosensitivity of oesophageal cancer cell lines.
Oesophageal cancer remains a poor-prognosis disease with a five-year survival of 20 %. Chemoresistance poses a significant challenge, and its mechanisms remain unclear. Our previous study found that the ISGylation network is differentially expressed in drug-sensitive and resistant oesophageal cancer cells. ISGylation involves conjugating Interferon-Stimulated Gene 15 (ISG15) to target proteins, regulated by E1, E2, and E3 enzymes, similar to ubiquitin. Ubiquitin Specific Peptidase 18 (USP18) removes ISG15 and negatively regulates the type I interferon (IFN) response. We investigated whether USP18 expression influences the chemosensitivity of two resistant oesophageal cancer cell lines. Treatment with IFN-α ( ± 5-fluorouracil (5-FU) or oxaliplatin) induces ISGylation network proteins, including USP18. ISG15 conjugation is only detected after USP18 depletion with siRNA. Silencing USP18 significantly increased sensitivity to 5-FU and oxaliplatin, inducing extensive apoptosis in both cell lines previously regarded as apoptosis incompetent. USP18 depletion also elevated LC3 II expression and autophagosome formation induced by IFN-α ( ± chemotherapeutic agents), indicative of autophagy. These findings demonstrate that strategies to inhibit USP18 could re-engage cell death signalling and restore sensitivity to chemo-resistant oesophageal cancer cells.
期刊介绍:
Our scope includes but is not limited to areas such as: Chromosome biology; Chromatin and epigenetics; DNA repair; Gene regulation; Nuclear import-export; RNA processing; Non-coding RNAs; Organelle biology; The cytoskeleton; Intracellular trafficking; Cell-cell and cell-matrix interactions; Cell motility and migration; Cell proliferation; Cellular differentiation; Signal transduction; Programmed cell death.