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5-Aza-2′-Deoxycytidine Improves the Sensitivity of Endometrial Cancer Cells to Progesterone Therapy

Hu, Qian PhD*; Yu, Li PhD*; Chen, Rui MD*; Wang, Yan-ling PhD; Ji, Lei PhD; Zhang, Yan PhD*; Xie, Ya PhD*; Liao, Qin-ping PhD*

International Journal of Gynecological Cancer: July 2012 - Volume 22 - Issue 6 - p 951–959
doi: 10.1097/IGC.0b013e3182540160
Basic Science

Objective: Progesterone has been proven to have limited effects on endometrial cancers (ECs), mainly owing to the down-regulation of progesterone receptor (PR). Here, we explored whether 5-aza-2′-deoxycytidine (5-aza-CdR), a demethylating agent, could enhance the susceptibility of EC cells to medroxyprogesterone acetate (MPA).

Methods: Ishikawa and KLE cell lines were treated with 5-aza-CdR and/or MPA. The expression of PR, PR target genes, and matrix metalloproteinase (MMP) was investigated by real-time polymerase chain reaction and Western blot. Promoter methylation was detected by methylation-specific polymerase chain reaction. The effects of 5-aza-CdR and/or MPA on cell proliferation, apoptosis, and invasion of EC cells were evaluated by 2-(4-Iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium assay, flow cytometry, invasion assay, and gelatin zymography, respectively.

Results: 5-Aza-2′-deoxycytidine significantly increased the expression of PR and its downstream targets by demethylating PR promoter in both Ishikawa and KLE cells. 5-Aza-2′-deoxycytidine combined with MPA synergistically suppressed the EC cell growth by inducing cell cycle arrest at G2/M phase and apoptosis. Furthermore, 5-aza-CdR synergized with MPA to inhibit the invasion of EC cells, perhaps owing to the down-regulation of MMP-2 and MMP-9 expression and activity.

Conclusions: 5-Aza-2′-deoxycytidine and MPA synergistically inhibit EC cell growth and invasion. Their combined use may provide a new effective therapeutic opportunity for endometrial carcinoma.

*Department of Obstetrics and Gynecology, Peking University First Hospital; and †State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.

Address correspondence and reprint requests to Qin-ping Liao, PhD, Department of Obstetrics and Gynecology, Peking, University First Hospital, No.8 Xishiku St, West District, Beijing 100034. E-mail: qinping_liao@163.com.

This study was supported by a grant from the General Program of National Natural Science Foundation of PR China (30672225).

The authors declare that there are no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal’s Web site (www.ijgc.net).

Received February 8, 2012

Accepted March 5, 2012

Copyright © 2012 by IGCS and ESGO