Targeting Nicotinamide N-Methyltransferase and miR-449a in EGFR-TKI-Resistant Non-Small-Cell Lung Cancer Cells

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 o...

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Veröffentlicht in:Molecular therapy. Nucleic acids 2018-06, Vol.11 (C), p.455-467
Hauptverfasser: Bach, Duc-Hiep, Kim, Donghwa, Bae, Song Yi, Kim, Won Kyung, Hong, Ji-Young, Lee, Hye-Jung, Rajasekaran, Nirmal, Kwon, Soonbum, Fan, Yanhua, Luu, Thi-Thu-Trang, Shin, Young Kee, Lee, Jeeyeon, Lee, Sang Kook
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Sprache:eng
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Zusammenfassung: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. [Display omitted]
ISSN:2162-2531
2162-2531
DOI:10.1016/j.omtn.2018.03.011