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.