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
- Medroxyprogesterone acetate
- DNA methylation
Statistics from Altmetric.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.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.