Open AccessABCC11/MRP8 confers pemetrexed resistance in lung cancer
Author(s) -
Uemura Takehiro,
Oguri Tetsuya,
Ozasa Hiroaki,
Takakuwa Osamu,
Miyazaki Mikinori,
Maeno Ken,
Sato Shigeki,
Ueda Ryuzo
Publication year - 2010
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2010.01690.x
Subject(s) - pemetrexed , lung cancer , medicine , oncology , cancer , cancer research , chemotherapy , cisplatin
We have previously shown that overexpression of thymidylate synthetase (TS) resulted in pemetrexed (MTA) resistance. To investigate another mechanism of MTA resistance, we investigated the expression of ATP‐binding cassette (ABC)‐transporters in MTA‐resistant lung cancer cell lines and found that the gene and protein expression of ABCC11/MRP8 (ABCC11) was higher in MTA‐resistant cells than in the parental cells. The MTA resistant cells showed cross‐resistance to methotrexate (MTX), which is a substrate for ABCC11, and intracellular MTX accumulation in MTA‐resistant cells was lower than in the parental cells. We then tested the effect of decreasing the expression of ABCC11 by siRNA and found that decreased expression of ABCC11 enhanced MTA cytotoxicity and increased intracellular MTX accumulation in MTA‐resistant cells. These findings suggested that ABCC11 directly confers resistance to MTA by enhancing efflux of the intracellular anti‐cancer drug. Next, we analyzed the relationship between ABCC11 gene expression and MTA sensitivity of 13 adenocarcinoma cells, but there was no correlation. The ABCC11 gene has been shown to have a functional single‐nucleotide polymorphism (SNP), 538G>A. We then classified 13 lung adenocarcinoma cell lines into three groups based on the genotype of this ABCC11 SNP: G/G, G/A and A/A. The A/A group showed a significant reduction in the IC 50 of MTA compared with the combined G/G and G/A groups, indicating that the SNP (538G>A) in the ABCC11 gene is an important determinant of MTA sensitivity. These results showed that ABCC11 may be one of the biomarkers for MTA treatment in adenocarcinomas. ( Cancer Sci 2010; 101: 2404–2410)