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5-Aza-2′-Deoxycytidine Improves the Sensitivity of Endometrial Cancer Cells to Progesterone Therapy
  1. Qian Hu, PhD*,
  2. Li Yu, PhD*,
  3. Rui Chen, MD*,
  4. Yan-ling Wang, PhD,
  5. Lei Ji, PhD,
  6. Yan Zhang, PhD*,
  7. Ya Xie, PhD* and
  8. Qin-ping Liao, PhD*
  1. *Department of Obstetrics and Gynecology, Peking University First Hospital; and
  2. State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
  1. 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{at}163.com.

Abstract

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.

  • Endometrial cancer
  • Progesterone receptor
  • 5-aza-2′-deoxycytidine
  • Medroxyprogesterone acetate
  • DNA methylation

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Footnotes

  • 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.

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