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Induction of methionine adenosyltransferase 2A in tamoxifen-resistant breast cancer cells

Title
Induction of methionine adenosyltransferase 2A in tamoxifen-resistant breast cancer cells
Author
김영미
Keywords
tamoxifen resistance; miR-146b; MAT2A; NF-kappa B; PTEN; NF-KAPPA-B; HUMAN LIVER-CANCER; S-ADENOSYLMETHIONINE; GASTRIC-CARCINOMA; MCF-7 CELLS; GROWTH; EXPRESSION; ACTIVATION
Issue Date
2016-03
Publisher
IMPACT JOURNALS LLC
Citation
ONCOTARGET, v. 7, No. 12, Page. 13902-13916
Abstract
We previously showed that S-adenosylmethionine-mediated hypermethylation of the PTEN promoter was important for the growth of tamoxifen-resistant MCF-7 (TAMR-MCF-7) cancer cells. Here, we found that the basal expression level of methionine adenosyltransferase 2A (MAT2A), a critical enzyme for the biosynthesis of S-adenosylmethionine, was up-regulated in TAMR-MCF-7 cells compared with control MCF-7 cells. Moreover, the basal expression level of MAT2A in T47D cells, a TAM-resistant estrogen receptor-positive cell line was higher compared to MCF-7 cells. Immunohistochemistry confirmed that MAT2A expression in TAM-resistant human breast cancer tissues was higher than that in TAM-responsive cases. The promoter region of human MAT2A contains binding sites for nuclear factor-kappa B, activator protein-1 (AP-1), and NF-E2-related factor 2 (Nrf2), and the activities of these three transcription factors were enhanced in TAMR-MCF-7 cells. Both the protein expression and transcriptional activity of MAT2A in TAMR-MCF-7 cells were potently suppressed by NF-kappa B inhibition but not by c-Jun/AP-1 or Nrf2 knock-down. Interestingly, the expression levels of microRNA (miR)-146a and -146b were diminished in TAMR-MCF-7 cells, and miR-146b transduction decreased NF-kappa B-mediated MAT2A expression. miR-146b restored PTEN expression via the suppression of PTEN promoter methylation in TAMR-MCF-7 cells. Additionally, miR-146b overexpression inhibited cell proliferation and reversed chemoresistance to 4-hydroxytamoxifen in TAMR-MCF-7 cells.
URI
http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=5298&path[]=14596http://repository.hanyang.ac.kr/handle/20.500.11754/102183
ISSN
1949-2553
DOI
10.18632/oncotarget.5298
Appears in Collections:
COLLEGE OF PHARMACY[E](약학대학) > PHARMACY(약학과) > Articles
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