PDF(Pubmed)
Abstract：
Urothelial cancer (UC) is a common malignancy and its development is associated with arsenic exposure. Around 25% of diagnosed UC cases are muscle invasive (MIUC) and are frequently associated with squamous differentiation. These patients commonly develop cisplatin (CIS) resistance and have poor prognosis. SOX2 expression is correlated to reduced overall and disease-free survival in UC. SOX2 drives malignant stemness and proliferation in UC cells and is associated with development of CIS resistance. Using quantitative proteomics, we identified that SOX2 was overexpressed in three arsenite (As3+)-transformed UROtsa cell lines. We hypothesized that inhibition of SOX2 would reduce stemness and increase sensitivity to CIS in the As3+-transformed cells. Pevonedistat (PVD) is a neddylation inhibitor and is a potent inhibitor of SOX2. We treated non-transformed parent and As3+-transformed cells with PVD, CIS, or in combination and monitored cell growth, sphere forming abilities, apoptosis, and gene/protein expression. PVD treatment alone caused morphological changes, reduced cell growth, attenuated sphere formation, induced apoptosis, and elevated the expression of terminal differentiation markers. However, the combined treatment of PVD with CIS significantly elevated the expression of terminal differentiation markers and eventually led to more cell death than either solo treatment. Aside from a reduced proliferation rate, these effects were not seen in the parent. Further research is needed to explore the potential use of PVD with CIS as a differentiation therapy or alternative treatment for MIUC tumors that may have become resistant to CIS.
摘要：
尿路上皮癌（UC）是一种常见的恶性肿瘤，其发展与砷暴露有关。约25％的诊断UC病例是肌肉侵入性（MIUC），通常与鳞状分化有关。这些患者通常发生顺铂（CIS）耐药性，预后不良。SOX2表达与UC的总体和无病生存率降低相关。SOX2驱动UC细胞的恶性干性和增殖，并与CIS抗性的发展有关。使用定量蛋白质组学，我们确定SOX2在三种亚砷酸盐（As3）转化的UROtsa细胞系中过表达。我们假设SOX2的抑制将降低干性并增加As3转化细胞中对CIS的敏感性。Pevonedistat（PVD）是一种neddylation抑制剂，是SOX2的有效抑制剂。我们用PVD处理未转化的亲本和As3+转化的细胞，CIS,或结合并监测细胞生长，球体形成能力，凋亡，和基因/蛋白质表达。单纯PVD治疗引起形态学改变,细胞生长减少,衰减球体形成，诱导细胞凋亡，并提高了终末分化标记的表达。然而,PVD与CIS的联合治疗显着提高了终末分化标志物的表达，并最终导致比单独治疗更多的细胞死亡。除了增殖速率降低,这些影响在父母中没有看到。需要进一步的研究来探索PVD与CIS作为可能对CIS耐药的MIUC肿瘤的分化疗法或替代治疗的潜在用途。
