Nicotinamide N-methyltransferase enhances resistance to 5-fluorouracil in colorectal cancer cells through inhibition of the ASK1-p38 MAPK pathway

• Published in: Oncotarget 2016-07, Vol.7 (29), p.45837-45848
• Main Authors: Xie, Xinyou, Liu, Huixing, Wang, Yanzhong, Zhou, Yanwen, Yu, Haitao, Li, Guiling, Ruan, Zhi, Li, Fengying, Wang, Xiuhong, Zhang, Jun
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - metabolism; Animals; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Colorectal Neoplasms - metabolism; Drug Resistance, Neoplasm - physiology; Fluorouracil - pharmacology; Humans; MAP Kinase Kinase Kinase 5 - metabolism; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; Mice; Mice, Nude; Nicotinamide N-Methyltransferase - metabolism; Research Paper; Xenograft Model Antitumor Assays
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.9962

Nicotinamide N-methyltransferase (NNMT), which converts nicotinamide to 1-methylnicotinamide (1-MNA), is overexpressed in a variety of human cancers and serves as a potential anti-cancer target. In this study, we investigated the effect of NNMT on 5-fluorouracil (5-FU) sensitivity of colorectal cancer (CRC) cells, and the underlying mechanisms. Our results show that down-regulation of NNMT in CRC HT-29 cells diminishes 5-FU resistance, while over expression of NNMT in SW480 cells enhances it. NNMT reduces reactive oxygen species (ROS) production induced by 5-FU by increasing 1-MNA in CRC cells. The reduction in ROS leads to inactivation of the ASK1-p38 mitogen-activated protein kinase (MAPK) pathway, which reduces 5-FU-induced apoptosis. In vivo, NNMT attenuates 5-FU-induced inhibition of CRC tumor growth in nude mice. These observations suggest that NNMT and the 1-MNA it produces inhibit the ASK1-p38 MAPK pathway, resulting in increased CRC cell resistance to 5-FU.