title: SIRT1-mediated FoxO1 deacetylation is essential for multidrug resistance-associated protein 2 expression in tamoxifen-resistant breast cancer cells.
abstract: Our previous studies have shown that multidrug resistance protein 2 (MRP2) is overexpressed in tamoxifen-resistant MCF-7 breast cancer cells (TAMR-MCF-7 cells) and forkhead box-containing protein, O subfamily1 (FoxO1), functions as a key regulator of multidrug resistance 1 (MDR1) gene transcription. This study aimed to investigate the role of FoxO1 in regulating MRP2 gene expression in TAMR-MCF-7 cells. The proximal promoter region of the human MRP2 gene contains four putative FoxO binding sites, and MRP2 gene transcription was stimulated by FoxO1 overexpression in MCF-7 cells. Subcellular fractionation and immunoblot analyses revealed that basal MRP2 expression and nuclear levels of FoxO1 were enhanced in TAMR-MCF-7 cells compared to MCF-7 cells and the enhanced MRP2 gene transcription was suppressed by FoxO1 siRNA. Because nuclear localization of FoxO1 is regulated by SIRT1 deacetylase, we were further interested in whether SIRT1 is involved in MRP2 expression. Overexpression of SIRT1 with FoxO1 potentiated the gene transcriptional activity of MRP2, and the basal activity and expression of SIRT1 was increased in TAMR-MCF-7 cells. In addition, SIRT1 inhibition reduced both the nuclear FoxO1 levels and MRP2 expression and enhanced cytotoxic effects of paclitaxel and doxorubicin in TAMR-MCF-7 cells. These results suggest that FoxO1 activation via SIRT1-mediated deacetylation is closely related with up-regulation of MRP2 in TAMR-MCF-7 cells.
authors.affiliation: BK21 Project Team, College of Pharmacy, Chosun University , Gwangju 501-759, South Korea.
authors.forename: Hoo-Kyun
authors.initials: HK
authors.lastname: Choi
authors.forename: Kyoung Bin
authors.initials: KB
authors.lastname: Cho
authors.forename: Nguyen Thi Thuy
authors.initials: NT
authors.lastname: Phuong
authors.forename: Chang Yeob
authors.initials: CY
authors.lastname: Han
authors.forename: Hyo-Kyung
authors.initials: HK
authors.lastname: Han
authors.forename: Tran Thi
authors.initials: TT
authors.lastname: Hien
authors.forename: Hong Seok
authors.initials: HS
authors.lastname: Choi
authors.forename: Keon Wook
authors.initials: KW
authors.lastname: Kang
mesh_terms: D000107:Acetylation / Q000187:drug effects; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D061986:MCF-7 Cells; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D056564:Sirtuin 1; D013629:Tamoxifen; C000715087:ABCC2 protein, human; C085126:FOXO1 protein, human; C447939:SIRT1 protein, human