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。

IF 3.5 3区 生物学 Q3 CELL BIOLOGY
M M Carey, T R O'Donovan, C M Coveney, S L McKenna
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引用次数: 0

摘要

食管癌仍然是一种预后不良的疾病,5年生存率为20%。化疗耐药是一个重大挑战,其机制尚不清楚。我们之前的研究发现,isg酰化网络在药物敏感和耐药食管癌细胞中存在差异表达。isg酰化涉及将干扰素刺激基因15 (ISG15)偶联到靶蛋白上,由E1、E2和E3酶调节,类似于泛素。泛素特异性肽酶18 (USP18)去除ISG15并负向调节干扰素(IFN)反应。我们研究了USP18表达是否影响两种耐药食管癌细胞系的化疗敏感性。IFN-α(+/- 5-氟尿嘧啶(5-FU)或奥沙利铂)治疗可诱导isgayylation网络蛋白,包括USP18。ISG15的结合仅在USP18用siRNA耗尽后检测到。沉默USP18显著增加了对5-FU和奥沙利铂的敏感性,在这两种先前被认为不凋亡的细胞系中诱导了广泛的细胞凋亡。USP18缺失也升高了IFN-α(+/-化疗药物)诱导的LC3 II表达和自噬体的形成,表明自噬。这些发现表明,抑制USP18的策略可以重新激活细胞死亡信号并恢复对化疗耐药食管癌细胞的敏感性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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.

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来源期刊
Experimental cell research
Experimental cell research 医学-细胞生物学
CiteScore
7.20
自引率
0.00%
发文量
295
审稿时长
30 days
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.
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