Project Details
Abstract
Estrogens induce cell proliferation through both nuclear estrogen receptors (ER)
or extra-nuclear GPR30/GPER1 receptor. In general, classic ER takes a longer time
to induce cell proliferation (24 hours or longer) whereas intracellular signals through
GPR30/GPER1 takes only a few minutes (5-60 min) and frequently co-regulated by
other growth factors.
The endometrium is a target tissue of estrogens. Through estrogen receptor
(ER), estrogens stimulate proliferation of the endometrial cell. In addition, estrogens
and antiestrogens may activate other growth factor receptors such as IGF-1R and
EGFR which in turn stimulate the phosphrylation of down-stream kinases, leading to
cell proliferation. Among the intracellular signal pathways, mammalian target of
rapamycin (mTOR) is one of molecules which may be phosphorylated by treatment
with estrogens and antiestrogens. Furthermore, nucleophosmin (NPM/B23), a
nucleolar protein acting as a stimulator to synthesize ribosome proteins, is found to
be responded to estrogens and induce cell proliferation. Recently, a novel link
among the estrogens/antiestrogens, mTOR and NPM/B23 has been delineated,
suggesting the importance of cross-talk among these elements.
Recently, we have successfully established immortalized human endometrial
cells by infection of endometrial cells with retrovirus containing human telomerase
reverse transcriptase (hTERT) (國科會計劃NSC96-2314-B- 182-016;PI:王馨世).
While an increasing number of observations suggest potential convergence between
these pathways, no direct evidence of their functional interaction has been reported.
Our previous studies showed that a number of endometrial cancer cell lines induced
phosphrylation of mTOR after treatment with estradiol or 4-OH-tamoxifen.
Additionally, the increased phosphrylation of Akt was also found after treatment
with estradiol or 4-OH-tamoxifen. In the next three years, we are going to perform
the following studies using immortalized endometrial cells, endometrial cancer cell
lines, and freshly cultured endometrial cells and endometrial cancer cells from
clinical specimens.
Part I (the first year): The study of mTOR pathway and production of
NPM/B23 in estrogen and antiestrogen-indeced cell proliferation through
GPR30/GPER1.
The aim of the first year of this study is to testify
1. if estrogen and antiestrogen enhance the phosphrylation of m-TOR (Ser2481 and
Ser2448), and p70S6K (a down-stream molecule of mTOR pathway?
2. if estrogen and antiestrogen may induce production of NPM/B23?
3. if estrogen and antiestrogen-induced phosphrylation of m-TOR (Ser2481 and
Ser2448), and p70S6K may diminish after knock-down of GPR30/GPER1 by
siRNA?
4. if estrogen and antiestrogen-induced phosphrylation of p70S6K may
diminish by addition of m-TOR inhibitors?
5. if estrogen and antiestrogen-induced production of NPM/B23 may diminish by
addition of m-TOR inhibitors?
6. if estrogen and antiestrogen-induced cell proliferation may diminish after
knock-down of NPM/B23 by siRNA?
Part II (the second year): The study of cross-talk of PI3K, ERK and Akt in
activation of mTOR signal pathway by estrogen and antiestrogen .
The aim of the second year of this study is to testify
1. if estrogen and antiestrogen enhance the phosphrylation of PI3K, ERK and
Akt in EGFR signal pathway?
2. if estrogen and antiestrogen-induced phosphrylation of m-TOR (Ser2481 and
Ser2448), and p70S6K may diminish by addition of inhibitors for PI3K,
ERK and Akt…?
3. if estrogen and antiestrogen-induced production of NPM/B23 may diminish
by addition of inhibitors for PI3K, ERK and Akt…?
Part III (the third year): The study of involvement of mTOR pathway
modulated by estrogens and progestins in decidualization of immortalized
endometrial cells.
The aim of the third year of this study is to testify
1. if progesterone inhibits the phosphrylation of m-TOR (Ser2481 and Ser2448),
and p70S6K (a down-stream molecule of mTOR pathway?
2. if progesterone reduces the production of NPM/B23 through blockade of m-TOR
pathway?
if progesterone-induced decidualization is through m-TOR pathway by induce
autophage pathway molecules (LC-3 and beclin-1)?
Project IDs
Project ID:PC10101-2085
External Project ID:NSC100-2314-B182-015-MY3
External Project ID:NSC100-2314-B182-015-MY3
Status | Finished |
---|---|
Effective start/end date | 01/08/12 → 31/07/13 |
Keywords
- estrogen receptor (ER)
- G protein-coupled receptor 30/G protein-coupled estrogen receptor 1 (GPR30/GPER1)
- mammalian target of rapamycin (mTOR)
- nucleophosmin (NPM/B23)
- immortalized endometrial cells.
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