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Neddylation inhibitor MLN4924 sensitizes head and neck squamous carcinoma cells to (S)-10-hydroxycamptothecin.

ABSTRACT: 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.

SUBMITTER: Gu S

PROVIDER: S-EPMC10492332 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Neddylation inhibitor MLN4924 sensitizes head and neck squamous carcinoma cells to (S)-10-hydroxycamptothecin.

Gu Shanshan S Lin Chen C Li Yanguo Y Wei Zhengyu Z Cao Bing B Shen Zhisen Z Deng Hongxia H

European journal of medical research 20230909 1

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 va ...[more]

PMID: 37689760

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Project description:Background: Head and neck squamous carcinoma (HNSC) is one of the most common malignant tumors with high incidence and poor prognosis. Transmembrane emp24 structural domain (TMED) proteins are involved in protein transport and vesicle budding processes, which have implicated various malignancies' progression. However, the roles of TMEDs in HNSC, especially in terms of development and prognosis, have not been fully elucidated. Methods: We applied TIMER 2.0, UALCAN, GEPIA 2, Kaplan-Meier plotter, GEO, The Human Protein Atlas (HPA), cBioPortal, Linkedomics, Metascape, GRNdb, STRING, and Cytoscape to investigate the roles of TMED family members in HNSC. Results: Compared with normal tissues, the mRNA expression levels of TMED1/2/4/5/7/8/9/10 were significantly increased in the TCGA HNSC dataset. And we combined GEPIA 2 and Kaplan-Meier Plotter to select TMED2/9/10 with prognostic value. Then we detected the levels of mRNA in the GEO HNSC database and the protein expression in HPA. It was found that the mRNA and protein expression levels of TMED2/9/10 were increased in HNSC. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that TMED2/9/10 and their co-expressed genes promoted the malignant behavior of tumors by participating in biological processes such as intracellular transferase complex, protein transport, focal adhesion, intracellular protein processing. Single-cell analysis and immune infiltration analysis suggested that immune responses of cancer-associated fibroblasts and endothelial cells might be associated with prognosis. Finally, the transcription factors-genes network and protein-protein functional interaction network pointed to genes such as X-box binding protein 1 (XBP1) and TMED7, which might cooperate with TMED2/9/10 to change the progression of HNSC. Conclusions: Our study implied that TMED2/9/10 and related genes mightjointly affect the prognosis of HNSC, providing specific clues for further experimental research, personalized diagnosis strategies, and targeted clinical therapy for HNSC.

Dataset Information

Neddylation inhibitor MLN4924 sensitizes head and neck squamous carcinoma cells to (S)-10-hydroxycamptothecin.

Publications

Neddylation inhibitor MLN4924 sensitizes head and neck squamous carcinoma cells to (S)-10-hydroxycamptothecin.

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