Chemotherapy remains one of the most important adjuvant treatments for bladder cancer (BC). However, similar to other malignancies, BC is prone to chemotherapy resistance and only approximately half of muscle‑invasive patients with BC respond to chemotherapy. The present study aimed to reveal the mechanisms underlying chemoresistance in BC cells. Cell viabilities were assessed by CCK‑8 assay. The differentiated expression of genes in chemoresistant and their parental BC cells were examined by RNA sequencing. Cell death was determined by flow cytometry. Different cell death inhibitors were used to determine the types of cell death. Levels of reactive oxygen species, iron, glutathione and malondialdehyde were assessed using the corresponding commercial kits. ChIP and dual luciferase activity assays were performed to investigate the interaction between staphylococcal nuclease and tumour domain containing 1 (SND1) and glutathione peroxidase 4 (GPX4) mRNA. RNAi was used to knockdown SND1 or GPX4. The results revealed that SND1 in BC cells were insensitive to cisplatin, and inhibition of SND1 overcame this resistance. Silencing of SND1 enhanced cell death induced by cisplatin by promoting ferroptosis in BC cells. Mechanistically, SND1 was revealed to bind to the 3'UTR region of GPX4 mRNA and stabilise it. Knockdown of GPX4 could also overcome chemoresistance, and overexpressing GPX4 reversed the effects of silencing of GPX4 on the chemosensitivity of BC cells. Thus, targeting the SND1‑GPX4 axis may be a potential strategy to overcome chemoresistance in BC cells.

中文翻译：

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抑制 SND1 通过促进铁死亡克服膀胱癌细胞的化学耐药性。

化疗仍然是膀胱癌 (BC) 最重要的辅助治疗之一。然而，与其他恶性肿瘤相似，BC 容易产生化疗耐药性，只有大约一半的肌肉浸润性 BC 患者对化疗有反应。本研究旨在揭示 BC 细胞化学耐药性的潜在机制。通过 CCK-8 测定法评估细胞活力。通过 RNA 测序检查化学抗性基因及其亲本 BC 细胞中基因的差异表达。通过流式细胞术确定细胞死亡。使用不同的细胞死亡抑制剂来确定细胞死亡的类型。使用相应的商业试剂盒评估活性氧、铁、谷胱甘肽和丙二醛的水平。进行 ChIP 和双荧光素酶活性测定以研究葡萄球菌核酸酶和含有 1 (SND1) 和谷胱甘肽过氧化物酶 4 (GPX4) mRNA 的肿瘤结构域之间的相互作用。RNAi 用于击倒 SND1 或 GPX4。结果表明，BC 细胞中的 SND1 对顺铂不敏感，抑制 SND1 克服了这种抗性。SND1 的沉默通过促进 BC 细胞的铁死亡来增强顺铂诱导的细胞死亡。从机制上讲，SND1 被发现与 GPX4 mRNA 的 3'UTR 区域结合并使其稳定。GPX4 的敲低也可以克服化学耐药性，并且过表达 GPX4 可以逆转 GPX4 沉默对 BC 细胞化学敏感性的影响。因此，靶向 SND1-GPX4 轴可能是克服 BC 细胞化学耐药性的潜在策略。