DCTPP1 attenuates the sensitivity of human gastric cancer cells to 5-fluorouracil by up-regulating MDR1 expression epigenetically.
Gastric cancer (GC) is among the most malignant cancers with high incidence and poor prognoses worldwide as well as in China. dCTP pyrophosphatase 1 (DCTPP1) is overexpressed in GC with a poor prognosis. Given chemotherapeutic drugs share similar structures with pyrimidine nucleotides, the role of DCTPP1 in affecting the drug sensitivity in GC remains unclear and is worthy of investigation. In the present study, we reported that DCTPP1-knockdown GC cell line BGC-823 exhibited more sensitivity to 5-fluorouracil (5-FU), demonstrated by the retardation of cell proliferation, the increase in cell apoptosis, cell cycle arrest at S phase and more DNA damages. Multidrug resistance 1 (MDR1) expression was unexpectedly down-regulated in DCTPP1-knockdown BGC-823 cells together with more intracellular 5-FU accumulation. This was in large achieved by the elevated methylation in promoter region of MDR1 gene. The intracellular 5-methyl-dCTP level increased in DCTPP1-knockdown BGC-823 cells as well. More significantly, the strong correlation of DCTPP1 and MDR1 expression was detectable in clinical GC samples. Our results thus imply a novel mechanism of chemoresistance mediated by the overexpression of DCTPP1 in GC. It is achieved partially through decreasing the concentration of intracellular 5-methyl-dCTP, which in turn results in promoter hypomethylation and hyper-expression of drug resistant gene MDR1. Our study suggests DCTPP1 as a potential indicative biomarker for the predication of chemoresistance in GC.
State Key Laboratory of Genetic Engineering, Department of Microbiology, School of Life Sciences and Institute of Biomedical Sciences, Fudan University, Shanghai, China.|Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China.
Li-Liang
LL
Xia
Shanghai Institute of Immunology, Department of Immunology and Microbiology, Department of Pharmacology and Chemical Biology, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Ya-Bin
YB
Tang
Shanghai Institute of Immunology, Department of Immunology and Microbiology, Department of Pharmacology and Chemical Biology, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Fei-Fei
FF
Song
Shanghai Institute of Immunology, Department of Immunology and Microbiology, Department of Pharmacology and Chemical Biology, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Ling
L
Xu
Shanghai Institute of Immunology, Department of Immunology and Microbiology, Department of Pharmacology and Chemical Biology, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Ping
P
Ji
Shanghai Institute of Immunology, Department of Immunology and Microbiology, Department of Pharmacology and Chemical Biology, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Shu-Jun
SJ
Wang
Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China.
Ji-Min
JM
Zhu
Shanghai Institute of Immunology, Department of Immunology and Microbiology, Department of Pharmacology and Chemical Biology, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Yong
Y
Zhang
State Key Laboratory of Genetic Engineering, Department of Microbiology, School of Life Sciences and Institute of Biomedical Sciences, Fudan University, Shanghai, China.|Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China.|Department of Microbiology and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China.
Guo-Ping
GP
Zhao
Shanghai Institute of Immunology, Department of Immunology and Microbiology, Department of Pharmacology and Chemical Biology, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Ying
Y
Wang
Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China.
Tao-Tao
TT
Liu
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects; D003845:Deoxycytosine Nucleotides / Q000378:metabolism; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011755:Pyrophosphatases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000964:Antimetabolites, Antineoplastic; D003845:Deoxycytosine Nucleotides; C034817:5-methyldeoxycytidine triphosphate; D011755:Pyrophosphatases; C020007:dCTP pyrophosphatase; D005472:Fluorouracil
5-methyl-dCTP; chemoresistance to 5-fluorouracil; dCTP pyrophosphatase 1; methylation; multidrug resistance 1