Pancreas · 2025
NAMPT Modulates Gemcitabine Resistance in Pancreatic Cancer via the p53 Signaling Pathway.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Xu Jia, Xu Wenchao, Liu Jianzhou, Zheng Ren, Zhang Xinmin, Wang Xuanqi, Yang Li, Zhou Li, Xiao Gary Guishan, Guo Junchao
Аннотация
OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed at an advanced stage. Although gemcitabine (GEM) is commonly used as the first-line chemotherapy, many patients eventually develop resistance. This study aims to investigate the role of nicotinamide phosphoribosyltransferase (NAMPT) in mediating gemcitabine resistance in PDAC, with a focus on identifying potential therapeutic targets within the nicotinate and nicotinamide metabolic pathways.
MATERIALS AND METHODS: We established the gemcitabine-resistant pancreatic cancer cell line BxPC-3-GR9 to simulate acquired resistance development. Subsequently, we conducted LC/MS metabolomics assays to identify altered metabolic pathways during gemcitabine resistance development. In addition, molecular and functional experiments targeting key enzymes in KEGG-enriched metabolic pathways to identify genes exhibiting significant changes. Mechanistically, transcriptome sequencing and molecular assays were employed to elucidate the regulatory mechanisms governing these target genes.
RESULTS: Compared with parent BxPC-3 cell lines, significant alterations in the nicotinate and nicotinamide metabolic pathways were found in BxPC-3-GR9. Furthermore, nicotinamide was the only metabolite shared during the enrichment process; higher expression of NAMPT was also detected in gemcitabine-resistant cell lines. NAMPT knockdown increased gemcitabine sensitivity in gemcitabine-resistant cells, which was validated in inherently resistant cell lines. Transcriptome analysis and molecular experiments demonstrated that NAMPT regulates the p53 signaling pathway via CCND1/2, contributing to gemcitabine resistance.
CONCLUSION: These findings suggest that NAMPT could serve as a promising therapeutic target to overcome gemcitabine resistance in PDAC, laying the groundwork for future clinical investigations aimed at modulating nicotinate and nicotinamide metabolism to improve treatment outcomes.
MATERIALS AND METHODS: We established the gemcitabine-resistant pancreatic cancer cell line BxPC-3-GR9 to simulate acquired resistance development. Subsequently, we conducted LC/MS metabolomics assays to identify altered metabolic pathways during gemcitabine resistance development. In addition, molecular and functional experiments targeting key enzymes in KEGG-enriched metabolic pathways to identify genes exhibiting significant changes. Mechanistically, transcriptome sequencing and molecular assays were employed to elucidate the regulatory mechanisms governing these target genes.
RESULTS: Compared with parent BxPC-3 cell lines, significant alterations in the nicotinate and nicotinamide metabolic pathways were found in BxPC-3-GR9. Furthermore, nicotinamide was the only metabolite shared during the enrichment process; higher expression of NAMPT was also detected in gemcitabine-resistant cell lines. NAMPT knockdown increased gemcitabine sensitivity in gemcitabine-resistant cells, which was validated in inherently resistant cell lines. Transcriptome analysis and molecular experiments demonstrated that NAMPT regulates the p53 signaling pathway via CCND1/2, contributing to gemcitabine resistance.
CONCLUSION: These findings suggest that NAMPT could serve as a promising therapeutic target to overcome gemcitabine resistance in PDAC, laying the groundwork for future clinical investigations aimed at modulating nicotinate and nicotinamide metabolism to improve treatment outcomes.