头颈鳞状细胞癌（HNSCC）是全球第七最常见的癌症。针对HNSCC的靶向治疗药物仍在探索中。其中，（S）-10-羟基喜树碱（10-HCPT）是一种TOP1的特异性抑制剂，通过DNA双链断裂可以抑制DNA复制并随后引发细胞凋亡性死亡。先前的研究已经报道了MLN4924通过抑制Cullin-RING连接酶并导致底物积累，在多种癌症中具有强力的抗肿瘤作用。在这里，我们展示了MLN4924有效地导致剂量依赖性的拓扑异构酶 I（TOP1）的积累，并阻止了TOP1的泛素化。重要的是，使用MLN4924抑制尼蒂化能够协同10-HCPT抑制HNSCC细胞的生长、迁移和凋亡。从机制上讲，转录组测序结果显示，MLN4924和10-HCPT的联合治疗的细胞毒作用可能涉及到NFKB1通路的激活。综上所述，我们的研究结果表明，MLN4924和10-HCPT的联合治疗可能是一种在HNSCC中有效的策略。©2023. 细胞出版社有限公司，Springer Nature的一部分。

Head and neck squamous carcinoma (HNSCC) is the seventh most common cancer worldwide. Targeted therapeutic drugs for HNSCC are still being explored. Among them, (S)-10-hydroxycamptothecin (10-HCPT), a specific inhibitor of TOP1, functions by DNA double-strand breaks that can inhibit DNA replication and trigger apoptotic cell death subsequently. Previous studies have reported that MLN4924 exerts potent anti-tumor effects by inhibiting cullin-RING ligases and causing substrate accumulation in a variety of cancers. Here, we show that MLN4924 effectively causes dose-dependent accumulation of topoisomerase I (TOP1) and blocks TOP1 ubiquitination. Importantly, neddylation inhibition with MLN4924 acts synergistically with 10-HCPT to suppress cell growth, migration and apoptosis in HNSCC cells. Mechanistically, transcriptome sequencing shows that the cytotoxic effects of the combination of MLN4924 and 10-HCPT may involve activation of the NFKB1 pathway. Taken together, our results suggest that combined treatment with MLN4924 and 10-HCPT may be an effective strategy in HNSCC.© 2023. BioMed Central Ltd., part of Springer Nature.