Estrogen-Induced Cell Proliferation through Mammalian Target of Rapamycin (Mtor) and Nucleophosmin (Npm/B23) in Endometrial Cells

  • Wang, Hsin-Shih (PI)
  • Chao, Angel (CoPI)
  • Wang, Tzu-Hao (CoPI)

Project: National Science and Technology CouncilNational Science and Technology Council Academic Grants

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
StatusFinished
Effective start/end date01/08/1231/07/13

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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