Targeting Nicotinamide N-Methyltransferase and miR-449a in EGFR-TKI-Resistant Non-Small-Cell Lung Cancer Cells
Autor: | Soonbum Kwon, Ji-Young Hong, Sang Kook Lee, Won Kyung Kim, Jeeyeon Lee, Nirmal Rajasekaran, Donghwa Kim, Hye-Jung Lee, Young Kee Shin, Duc-Hiep Bach, Thi-Thu-Trang Luu, Yanhua Fan, Song Yi Bae |
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Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
NNMT Nicotinamide N-methyltransferase medicine.disease_cause NSCLC Article 03 medical and health sciences 0302 clinical medicine EGFR-TKI Drug Discovery microRNA PTEN/PI3K/Akt Medicine Tensin PTEN Lung cancer yuanhuadine gefitinib resistance Gene knockdown biology business.industry lcsh:RM1-950 medicine.disease respiratory tract diseases 030104 developmental biology lcsh:Therapeutics. Pharmacology non-small-cell lung cancer Tumor progression 030220 oncology & carcinogenesis docking Cancer research biology.protein miR-449a Molecular Medicine methylation business Carcinogenesis |
Zdroj: | Molecular Therapy: Nucleic Acids, Vol 11, Iss C, Pp 455-467 (2018) Molecular Therapy. Nucleic Acids |
ISSN: | 2162-2531 |
Popis: | Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are used clinically as target therapies for lung cancer patients, but the occurrence of acquired drug resistance limits their efficacy. Nicotinamide N-methyltransferase (NNMT), a cancer-associated metabolic enzyme, is commonly overexpressed in various human tumors. Emerging evidence also suggests a crucial loss of function of microRNAs (miRNAs) in modulating tumor progression in response to standard therapies. However, their precise roles in regulating the development of drug-resistant tumorigenesis are still poorly understood. Herein, we established EGFR-TKI-resistant non-small-cell lung cancer (NSCLC) models and observed a negative correlation between the expression levels of NNMT and miR-449a in tumor cells. Additionally, knockdown of NNMT suppressed p-Akt and tumorigenesis, while re-expression of miR-449a induced phosphatase and tensin homolog (PTEN), and inhibited tumor growth. Furthermore, yuanhuadine, an antitumor agent, significantly upregulated miR-449a levels while critically suppressing NNMT expression. These findings suggest a novel therapeutic approach for overcoming EGFR-TKI resistance to NSCLC treatment. Graphical Abstract |
Databáze: | OpenAIRE |
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