MRP8/ABCC11 directly confers resistance to 5-fluorouracil.
Multidrug-resistance-associated protein, MRP8/ABCC11 (ABCC11), is an efflux pump for nucleotide analogues and 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP). To test whether ABCC11 directly confers 5-fluorouracil (5-FU) resistance, we used the 5-FU-resistant subline PC-6/FU23-26 selected from PC-6 human small-cell lung cancer cells by 5-FU and found that it increases the resistance by approximately 25-fold. The intracellular FdUMP accumulation was reduced in PC-6/FU23-26 cells concomitant with the overexpression of the ABCC11 gene. These findings suggest that ABCC11 confers 5-FU resistance in the sublines by enhancing the efflux for the active metabolite FdUMP. Previously, methotrexate also increased the efflux by ABCC11, and we found cross-resistance to methotrexate in PC-6/FU23-26 cells. To confirm our hypothesis, we examined whether decreasing the expression of ABCC11 in PC-6/FU23-26 cells by small interfering RNA altered the cytotoxicity to 5-FU and methotrexate and found that this enhanced 5-FU and methotrexate cytotoxicity in PC-6/FU23-26 cells. These data indicate that expression of the ABCC11 gene is induced by 5-FU, and that ABCC11 is directly involved in 5-FU resistance by the efflux transport of the active metabolite FdUMP.
Oguri
Tetsuya
T
Department of Internal Medicine and Molecular Science, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan. t-oguri@med.nagoya-cu.ac.jp
Bessho
Yuji
Y
Achiwa
Hiroyuki
H
Ozasa
Hiroaki
H
Maeno
Ken
K
Maeda
Hiroyoshi
H
Sato
Shigeki
S
Ueda
Ryuzo
R
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D040501:Calgranulin A / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005468:Fluorodeoxyuridylate / Q000378:metabolism; D005472:Fluorouracil / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000235:genetics; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D040501:Calgranulin A; D005468:Fluorodeoxyuridylate; D005472:Fluorouracil; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering