DHT对LNCaP细胞中FGF信号传导和细胞增殖的自分泌作用：肝素/乙酰肝素降解酶的作用。,The Prostate

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DHT对LNCaP细胞中FGF信号传导和细胞增殖的自分泌作用：肝素/乙酰肝素降解酶的作用。
The Prostate ( IF 2.6 ) Pub Date : 2000-07-06 , DOI: 10.1002/1097-0045(20000701)44:2<124::aid-pros5>3.0.co;2-s
A E Kassen ₁ , J A Sensibar , S M Sintich , S J Pruden , J M Kozlowski , C Lee

Affiliation

背景技术LNCaP细胞是雄激素敏感的人前列腺癌细胞。它们的特征是响应培养物中双氢睾丸激素（DHT）剂量的增加，呈钟形生长曲线。在低浓度的DHT（0.1 nM）下，这些细胞显示出增殖的增加，但是在高浓度（100 nM）的DHT下它们的生长被阻止了。我们先前研究的结果表明，高浓度DHT的抑制作用是通过TGF-beta1的作用介导的。本研究的目的是阐明DHT在LNCaP细胞中增殖作用的机制。方法和结果DHT仅在有血清的情况下培养细胞才能刺激LNCaP增殖。在无血清培养物中，未观察到DHT诱导的特征性增殖。添加针对FGF-2（碱性成纤维细胞生长因子）的中和抗体能够抑制这种DHT诱导的增殖。这些结果表明，DHT的增殖作用是通过FGF-2的作用介导的。但是，逆转录酶聚合酶链反应的结果表明LNCaP细胞不表达FGF-2信息。结果，这些培养物中FGF-2的来源必须是培养基中补充的血清。FGF-2可以与细胞外基质（ECM）中的肝素硫酸盐链结合。在用外源肝素处理的培养物中，DHT的增殖作用被消除。这些结果导致了以下假设的发展：DHT处理通过增加肝素酶活性来介导ECM中包裹的FGF-2的释放。在没有DHT的情况下，向LNCaP细胞培养物中添加肝素酶能够刺激细胞增殖。此外，0.1 nM DHT导致肝素酶活性显着增加。结论这些结果为DNC在LNCaP细胞中的作用提供了可能的机制。在没有DHT的情况下，培养物中的FGF-2被困在细胞外基质中，无法与LNCaP细胞相互作用。但是，在存在0.1 nM DHT的情况下，培养物中的肝素酶活性升高，结果，它释放了被捕获的FGF-2，进而刺激了LNCaP细胞的增殖。培养物中的FGF-2被捕获在细胞外基质中，无法与LNCaP细胞相互作用。但是，在存在0.1 nM DHT的情况下，培养物中的肝素酶活性升高，结果，它释放了被捕获的FGF-2，进而刺激了LNCaP细胞的增殖。培养物中的FGF-2被捕获在细胞外基质中，无法与LNCaP细胞相互作用。然而，在0.1 nM DHT的存在下，培养物中的肝素酶活性升高，结果，它释放了被捕获的FGF-2，进而刺激了LNCaP细胞的增殖。

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Autocrine effect of DHT on FGF signaling and cell proliferation in LNCaP cells: role of heparin/heparan-degrading enzymes.

BACKGROUND LNCaP cells are androgen-sensitive human prostate cancer cells. They are characterized by a bell-shaped growth curve in response to increasing doses of dihydrotestosterone (DHT) in culture. At a low concentration of DHT (0.1 nM), these cells show an increase in proliferation, but their growth is arrested at a high concentration (100 nM) of DHT. Results of our previous study demonstrated that the inhibitory effect of DHT at a high concentration was mediated through the action of TGF-beta1. The objective of the present study was to elucidate the mechanism of the proliferative effect of DHT in LNCaP cells. METHODS AND RESULTS DHT stimulated LNCaP proliferation only when cells were cultured in the presence of serum. In serum-free cultures, the characteristic DHT-induced proliferation was not observed. The addition of neutralizing antibody against FGF-2 (basic fibroblast growth factor) was able to inhibit this DHT-induced proliferation. These results suggest that the proliferative effect of DHT was mediated through the action of FGF-2. However, results of the reverse transcriptase polymerase chain reaction indicated that LNCaP cells did not express FGF-2 message. As a result, the source of FGF-2 in these cultures must be the serum supplemented in the culture media. FGF-2 can bind to heparin sulfate chains within the extracellular matrix (ECM). In cultures treated with exogenous heparin, the proliferative effect of DHT was abolished. These results led to the development of the hypothesis that DHT treatment mediates the release of FGF-2 entrapped in the ECM through increased heparinase activity. The addition of heparinase to cultures of LNCaP cells, in the absence of DHT, was able to stimulate cell proliferation. Moreover, 0.1 nM DHT caused a significant increase in heparinase activity. CONCLUSIONS These results provide a possible mechanism for DHT action in LNCaP cells. In the absence of DHT, FGF-2 in culture was trapped in the extracellular matrix and was not available to interact with LNCaP cells. However, in the presence of 0.1 nM DHT, heparinase activity in the culture was elevated and, as a result, it liberated the trapped FGF-2 which, in turn, stimulated proliferation in LNCaP cells.

更新日期：2019-11-01

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