Oncotarget

Research Papers:

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

Xinyou Xie _, Huixing Liu, Yanzhong Wang, Yanwen Zhou, Haitao Yu, Guiling Li, Zhi Ruan, Fengying Li, Xiuhong Wang and Jun Zhang

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Oncotarget. 2016; 7:45837-45848. https://doi.org/10.18632/oncotarget.9962

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Abstract

Xinyou Xie1,2, Huixing Liu1,2, Yanzhong Wang1,2, Yanwen Zhou1,2, Haitao Yu1,2, Guiling Li1,2, Zhi Ruan1,2, Fengying Li1,2, Xiuhong Wang1,2, Jun Zhang1,2

1Department of Clinical Laboratory, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China

2Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang 310016, P.R. China

Correspondence to:

Jun Zhang, email: [email protected]

Keywords: nicotinamide N-methyltransferase, 1-methylnicotinamide, 5-fluorouracil, colorectal cancer, p38 MAPK

Received: October 19, 2015    Accepted: May 30, 2016    Published: June 13, 2016

ABSTRACT

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.


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