Forkhead transcription factor FOXO1 is a direct target of progestin to inhibit endometrial epithelial cell growth.
OBJECTIVE
Despite the therapeutic utility of progestin in invasive and preinvasive endometrial neoplasias, the molecular mechanisms through which it exerts inhibitory effects on endometrial epithelial growth are largely unknown. The aim of the study was to clarify the molecular mechanisms of progestin action to endometrial epithelial cells using originally established in vitro and in vivo treatment models for immortalized and transformed endometrial epithelial cell lines that express progesterone receptor.


RESULTS
In this model, progestin effectively inhibited the cell growth, inducing G0/G1 arrest rather than apoptosis without p21/WAF-1 induction. Using DNA microarray analysis, we identified 24 genes whose expression increased more than 10-fold on progestin treatment. Of these genes, we paid special attention to forkhead box transcription factor FOXO1, known as a key gene for endometrial decidualization. Progestin markedly induced FOXO1 gene expression mainly in the nuclei in vitro and in vivo. This induction was not due to the canonical activation of FOXO1 via protein dephosphorylation but due to FOXO1 promoter activation and mRNA induction. siRNA inhibition of FOXO1 significantly attenuated the effects of progestin to inhibit endometrial epithelial cell growth. Disrupting Akt activity by the introduction of the dominant negative form of Akt increased nuclear FOXO1 accumulation and enhanced the effect of progestin.


CONCLUSIONS
These findings suggest that FOXO1 is a direct target of progestin, implicating novel molecular mechanisms of progestin to eradicate endometrial neoplasia.
Department of Obstetrics and Gynecology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan. satoruky@med.kanazawa-u.ac.jp
Satoru
S
Kyo
Junko
J
Sakaguchi
Tohru
T
Kiyono
Yutaka
Y
Shimizu
Yoshiko
Y
Maida
Yasunari
Y
Mizumoto
Noriko
N
Mori
Mitsuhiro
M
Nakamura
Masahiro
M
Takakura
Kiyohiko
K
Miyake
Masaru
M
Sakamoto
Masaki
M
Inoue
D000818:Animals; D002453:Cell Cycle; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004717:Endometrium / Q000166:cytology* / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects*; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011372:Progestins / Q000494:pharmacology*; D011980:Receptors, Progesterone / Q000378:metabolism; D015533:Transcriptional Activation
C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D011372:Progestins; D011980:Receptors, Progesterone