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男性ホルモンレセプターの囮分子が前立腺がん成長を阻止 Androgen Receptor Decoy Molecules Block The Growth Of Prostate Cancer
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Androgen Receptor Decoy Molecules Block The Growth Of Prostate Cancer
Main Category: Prostate / Prostate Cancer News
Article Date: 26 Feb 2007 - 0:00 PST
男性ホルモンレセプター（AR）は男性ホルモン感応型前立腺がんと男性ホルモン非感応型前立腺がんのいずれに関しても男性ホルモン関連遺伝子（例えばPSA)の活性化に中心的な役割を果たす。
ARの機能ドメイン(functional domain)にはC-terminal LBD（リガンド接着）というDNAに接着するドメインとN-terminalドメイン（NTD）がある。
男性ホルモンはLBDに接着し、その後、核に移動、男性ホルモン感応エレメント(ARE)の一部となる。AREは遺伝子の転写を活性化する。
男性ホルモンが欠如している場合、成長ファクターと言った別のファクターがNTDを活性化し、AREの一部となり、遺伝子転写を誘導することができる。
この研究では囮のNTD分子を作成して、以下の事実を明らかにした。すなわち、CaP細胞内の囮分子は、一人前に機能してタンパク質を相互に作用することでCaP成長を研究室及び動物モデルで減少させることを。
AR NTDのアミノ酸1-558を生成する構造物をLNCaP男性ホルモン感応型CaP細胞内に搬送された。
成長ファクターを追加後、PSAの数字は66％減少した。
これは囮のAR NTD が有効に成長ファクターと接着し、細胞の本来のARのNTDに接着する余地をほとんどなくすことによると思われる。
囮のNTDを発現するLNCaP 細胞が去勢していないマウスに移植され、制御されたものは100％のマウスが腫瘍を発生させたが、囮マウスは腫瘍発現率は58％であった。制御されたものでは５週でPSA発現が起きたが、囮マウスでは９週間、制御マウスのPSA水準は実験の終了時で10倍高かった。
UroToday.com- The androgen receptor (AR) is central to activation of androgen-regulated genes (such as PSA) in both androgen sensitive and androgen insensitive prostate cancer (CaP).
Functional domains in AR include a C-terminal ligand-binding domain (LBD), a DNA-binding domain and an N-terminal domain (NTD).
Androgen binds to the LBD, translocates to the nucleus and complexes to androgen-response elements (AREs), which activates gene transcription.
In the absence of androgen, other factors such as growth factors can activate the NTD to complex with AREs and induce gene transcription.
Dr. Quayle and research colleagues created decoy NTD molecules and found that expression of the decoy molecules in CaP cells competitively bound to interacting proteins and decreased CaP growth in laboratory and animal models. Their report appears in the January 23, 2007 issue of the Proceedings of the National Academy of Science.
A construct encoding amino acids 1-558 of the AR NTD was transfected into LNCaP androgen sensitive CaP cells.
It was expressed by the cells and upon addition of growth factors decreased PSA expression by 66%.
This would be due to the decoy AR NTD competitively binding the growth factor, leaving little to bind to the NTD of the cells' native AR.
LNCaP cells expressing the decoy NTD were implanted in intact (non-castrate) mice and while controls developed tumors in 100% of mice, the decoy mice had a tumor take rate of only 58%. Expression of PSA occurred at 5 weeks in controls as compared to 9 weeks in decoy mice and control mice had PSA levels ten times higher at the conclusion of the experiment. Tumor volume was four times larger in the control animals.
In castrated mice, the time to androgen-independence was evaluated. Castration resulted in a >90% decrease in serum PSA in all mice by 4 weeks. PSA began to rapidly rise in control mice, while the decoy group PSA remained <20% of the pre-castrate level throughout the duration of the experiment. Immunhistochemical staining of tumors for proliferation showed decreased proliferation in the decoy tumors. Apoptotic cell death was measured by TUNEL staining and showed that reduced decoy tumor growth was due to increased cell death in addition to decreased proliferation.
The use of decoy AR NTD inhibited androgen-dependent and androgen-independent expression of PSA and tumor growth. This innovative work models a strategy to treat androgen-independent CaP.
Androgen Receptor Decoy Molecules Block The Growth Of Prostate Cancer
Main Category: Prostate / Prostate Cancer News
Article Date: 26 Feb 2007 - 0:00 PST
男性ホルモンレセプター（AR）は男性ホルモン感応型前立腺がんと男性ホルモン非感応型前立腺がんのいずれに関しても男性ホルモン関連遺伝子（例えばPSA)の活性化に中心的な役割を果たす。
ARの機能ドメイン(functional domain)にはC-terminal LBD（リガンド接着）というDNAに接着するドメインとN-terminalドメイン（NTD）がある。
男性ホルモンはLBDに接着し、その後、核に移動、男性ホルモン感応エレメント(ARE)の一部となる。AREは遺伝子の転写を活性化する。
男性ホルモンが欠如している場合、成長ファクターと言った別のファクターがNTDを活性化し、AREの一部となり、遺伝子転写を誘導することができる。
この研究では囮のNTD分子を作成して、以下の事実を明らかにした。すなわち、CaP細胞内の囮分子は、一人前に機能してタンパク質を相互に作用することでCaP成長を研究室及び動物モデルで減少させることを。
AR NTDのアミノ酸1-558を生成する構造物をLNCaP男性ホルモン感応型CaP細胞内に搬送された。
成長ファクターを追加後、PSAの数字は66％減少した。
これは囮のAR NTD が有効に成長ファクターと接着し、細胞の本来のARのNTDに接着する余地をほとんどなくすことによると思われる。
囮のNTDを発現するLNCaP 細胞が去勢していないマウスに移植され、制御されたものは100％のマウスが腫瘍を発生させたが、囮マウスは腫瘍発現率は58％であった。制御されたものでは５週でPSA発現が起きたが、囮マウスでは９週間、制御マウスのPSA水準は実験の終了時で10倍高かった。
UroToday.com- The androgen receptor (AR) is central to activation of androgen-regulated genes (such as PSA) in both androgen sensitive and androgen insensitive prostate cancer (CaP).
Functional domains in AR include a C-terminal ligand-binding domain (LBD), a DNA-binding domain and an N-terminal domain (NTD).
Androgen binds to the LBD, translocates to the nucleus and complexes to androgen-response elements (AREs), which activates gene transcription.
In the absence of androgen, other factors such as growth factors can activate the NTD to complex with AREs and induce gene transcription.
Dr. Quayle and research colleagues created decoy NTD molecules and found that expression of the decoy molecules in CaP cells competitively bound to interacting proteins and decreased CaP growth in laboratory and animal models. Their report appears in the January 23, 2007 issue of the Proceedings of the National Academy of Science.
A construct encoding amino acids 1-558 of the AR NTD was transfected into LNCaP androgen sensitive CaP cells.
It was expressed by the cells and upon addition of growth factors decreased PSA expression by 66%.
This would be due to the decoy AR NTD competitively binding the growth factor, leaving little to bind to the NTD of the cells' native AR.
LNCaP cells expressing the decoy NTD were implanted in intact (non-castrate) mice and while controls developed tumors in 100% of mice, the decoy mice had a tumor take rate of only 58%. Expression of PSA occurred at 5 weeks in controls as compared to 9 weeks in decoy mice and control mice had PSA levels ten times higher at the conclusion of the experiment. Tumor volume was four times larger in the control animals.
In castrated mice, the time to androgen-independence was evaluated. Castration resulted in a >90% decrease in serum PSA in all mice by 4 weeks. PSA began to rapidly rise in control mice, while the decoy group PSA remained <20% of the pre-castrate level throughout the duration of the experiment. Immunhistochemical staining of tumors for proliferation showed decreased proliferation in the decoy tumors. Apoptotic cell death was measured by TUNEL staining and showed that reduced decoy tumor growth was due to increased cell death in addition to decreased proliferation.
The use of decoy AR NTD inhibited androgen-dependent and androgen-independent expression of PSA and tumor growth. This innovative work models a strategy to treat androgen-independent CaP.
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Latest page update: made by ishida
, Mar 12 2007, 5:32 AM EDT
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