Nicotinamide N-methyltransferase enhances resistance to 5-fluorouracil in colorectal cancer cells through inhibition of the ASK1-p38 MAPK pathway.
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.
Department of Clinical Laboratory, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China.|Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang 310016, P.R. China.
Xinyou
X
Xie
Department of Clinical Laboratory, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China.|Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang 310016, P.R. China.
Huixing
H
Liu
Department of Clinical Laboratory, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China.|Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang 310016, P.R. China.
Yanzhong
Y
Wang
Department of Clinical Laboratory, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China.|Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang 310016, P.R. China.
Yanwen
Y
Zhou
Department of Clinical Laboratory, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China.|Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang 310016, P.R. China.
Haitao
H
Yu
Department of Clinical Laboratory, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China.|Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang 310016, P.R. China.
Guiling
G
Li
Department of Clinical Laboratory, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China.|Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang 310016, P.R. China.
Zhi
Z
Ruan
Department of Clinical Laboratory, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China.|Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang 310016, P.R. China.
Fengying
F
Li
Department of Clinical Laboratory, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China.|Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang 310016, P.R. China.
Xiuhong
X
Wang
Department of Clinical Laboratory, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China.|Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang 310016, P.R. China.
Jun
J
Zhang
D000230:Adenocarcinoma / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D050903:Nicotinamide N-Methyltransferase / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C494406:NNMT protein, human; D050903:Nicotinamide N-Methyltransferase; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; D005472:Fluorouracil
1-methylnicotinamide; 5-fluorouracil; colorectal cancer; nicotinamide N-methyltransferase; p38 MAPK