CSC-3436 inhibits TWIST-induced epithelial-mesenchymal transition via the suppression of Twist/Bmi1/Akt pathway in head and neck squamous cell carcinoma.
Head and neck squamous cell carcinoma (HNSCC) is one of the leading causes of cancer deaths worldwide, especially in male. With poor prognosis, significant portions of patients with HNSCC die due to cancer recurrence and tumor metastasis after chemotherapy and targeted therapies. The HNSCC FaDu cell ectopic expression of Twist, a key transcriptional factor of epithelial-mesenchymal transition (EMT), which triggers EMT and results in the acquisition of a mesenchymal phenotype, was used as the cell model. Our results demonstrated that treatment with newly synthesized 2-(3-hydroxyphenyl)-5-methylnaphthyridin-4-one (CSC-3436), a flavonoid derivative, elicited changes in its cell morphology, upregulated E-cadherin messenger RNA and protein expression, downregulated N-cadherin, vimentin, and CD133 (a marker associated with tumor-initiating cells) in FaDu-pCDH-Twist cells. Moreover, CSC-3436 exposure reduced B cell-specific Moloney murine leukemia virus integration site 1 (Bmi1) expression regulated by Twist and further suppressed the direct co-regulation of E-cadherin by Twist and Bmi1. Interestingly, CSC-3436 reduced EMT, cancer stemness, and migration/invasion abilities through the inhibition of the Twist/Bmi1-Akt/β-catenin pathway. Most importantly, our findings provided new evidence that CSC-3436 played a crucial role in therapeutic targeting to Bmi1 and its molecular pathway in HNSCC, and it will be valuable in prognostic prediction and treatment.
['Lai|Ying-Ju|YJ|0000-0002-8423-8969', 'Yu|Wan-Nien|WN|', 'Kuo|Sheng-Chu|SC|', 'Ho|Chi-Tang|CT|', 'Hung|Chao-Ming|CM|', 'Way|Tzong-Der|TD|', 'Chen|Chiung-Tong|CT|']
D000818:Animals D015703:Antigens, CD D000970:Antineoplastic Agents D015820:Cadherins D045744:Cell Line, Tumor D002465:Cell Movement D058750:Epithelial-Mesenchymal Transition D005260:Female D015972:Gene Expression Regulation, Neoplastic D006258:Head and Neck Neoplasms D006801:Humans D016688:Mice, Inbred NOD D016513:Mice, SCID D009287:Naphthyridines D009361:Neoplasm Invasiveness D009687:Nuclear Proteins D063150:Polycomb Repressive Complex 1 D051057:Proto-Oncogene Proteins c-akt D015398:Signal Transduction D000077195:Squamous Cell Carcinoma of Head and Neck D051879:Twist-Related Protein 1 D023041:Xenograft Model Antitumor Assays
twist head and neck squamous cell carcinoma (HNSCC) epithelial-mesenchymal transition (EMT) 2-(3-hydroxyphenyl)-5-methylnaphthyridin-4-one (CSC-3436) B cell-specific Moloney murine leukemia virus integration site 1 (Bmi1)