FKBP51 and Cyp40 are positive regulators of androgen-dependent prostate cancer cell growth and the targets of FK506 and cyclosporin A.
FKBP51 and Cyp40 are positive regulators of androgen-dependent prostate cancer cell growth and the targets of FK506 and cyclosporin A.
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DOI：
10.1038/onc.2009.458
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发表时间：
2010-03-18
期刊：
影响因子：
8
通讯作者：
Sanchez, E. R.
中科院分区：
文献类型：
--
作者：
Periyasamy, S.;Hinds, T., Jr.;Shemshedini, L.;Shou, W.;Sanchez, E. R.
前列腺癌（PCa）的生长依赖于雄激素和雄激素受体（AR），其通过调节基因转录起作用。在PCa细胞中，三肽重复序列（TPR）蛋白（FKBP 52、FKBP 51和Cyp 40）与AR相互作用，提示其在AR介导的基因转录和细胞生长中的作用。我们在这里报告，FKBP 51和Cyp 40，但不是FKBP 52，在前列腺癌组织和雄激素依赖性（AD）和非依赖性（AI）细胞系显着升高。FKBP 51在AD LNCaP细胞中的过表达增加了雄激素存在和不存在下的AR转录活性，而FKBP 51的siRNA敲低显著降低了AD基因的转录和增殖。敲低Cyp 40也抑制LNCaP细胞中雄激素介导的转录和生长。然而，在AIC 4 -2细胞中FKBP 51和Cyp 40的破坏仅引起增殖的少量减少，表明Cyp 40和FKBP 51主要调节AD细胞增殖。在敲低条件下，未观察到TPR配体CsA和FK 506对AR活性的抑制作用，表明Cyp 40和FKBP 51分别是CsA和FK 506的靶点。我们的研究结果表明，FKBP 51和Cyp 40是AR的正调控因子，可以被CsA和FK 506选择性地靶向，以实现对雄激素诱导的细胞增殖的抑制。因此，这些蛋白质及其同源配体为前列腺癌的治疗提供了新的策略
Prostate cancer (PCa) growth is dependent on androgens and the androgen receptor (AR), which acts by modulating gene transcription. Tetratricopeptide repeat (TPR) proteins (FKBP52, FKBP51 and Cyp40) interact with AR in PCa cells, suggesting roles in AR-mediated gene transcription and cell growth. We report here that FKBP51 and Cyp40, but not FKBP52, are significantly elevated in PCa tissues and in androgen-dependent (AD) and -independent (AI) cell lines. Overexpression of FKBP51 in AD LNCaP cells increased AR transcriptional activity in the presence and absence of androgen, whereas siRNA knockdown of FKBP51 dramatically decreased AD gene transcription and proliferation. Knockdown of Cyp40 also inhibited androgen-mediated transcription and growth in LNCaP cells. However, disruption of FKBP51 and Cyp40 in the AI C4-2 cells caused only a small reduction in proliferation, indicating that Cyp40 and FKBP51 predominantly regulate AD cell proliferation. Under knock-down conditions, the inhibitory effects of TPR ligands, CsA and FK506, on AR activity were not observed, indicating that Cyp40 and FKBP51 are the targets of CsA and FK506, respectively. Our findings demonstrate that FKBP51 and Cyp40 are positive regulators of AR that can be selectively targeted by CsA and FK506 to achieve inhibition of androgen-induced cell proliferation. These proteins and their cognate ligands thus provide new strategies in the treatment of PCa
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影响因子：
6.6
作者：
Febbo, PG;Lowenberg, M;Golub, TR
通讯作者：
Golub, TR
影响因子：
2.9
作者：
Banerjee, Ananya;Periyasamy, Sumudra;Wolf, Irene M.;Hinds, Terry D., Jr.;Yong, Weidong;Shou, Weinian;Sanchez, Edwin R.
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Sanchez, Edwin R.
DOI：
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发表时间：
2005-08-01
影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
Hubler, TR;Denny, WB;Scammell, JG
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影响因子：
20.3
作者：
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通讯作者：
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