5-aza-2'-deoxycytidine improves the sensitivity of endometrial cancer cells to progesterone therapy.
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, Beijing, China.
Qian
Q
Hu
Li
L
Yu
Rui
R
Chen
Yan-ling
YL
Wang
Lei
L
Ji
Yan
Y
Zhang
Ya
Y
Xie
Qin-ping
QP
Liao
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000077209:Decitabine; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D006801:Humans; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology / Q000627:therapeutic use*; D009361:Neoplasm Invasiveness; D011980:Receptors, Progesterone / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D018931:Antineoplastic Agents, Hormonal; D011980:Receptors, Progesterone; C097314:progesterone receptor B; D000077209:Decitabine; D017258:Medroxyprogesterone Acetate; D001374:Azacitidine