Androgen-dependent regulation of Her-2/neu in prostate cancer cells
Androgen-dependent regulation of Her-2/neu in prostate cancer cells
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DOI：
10.1158/0008-5472.can-05-3928
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发表时间：
2006-06-01
期刊：
影响因子：
11.2
通讯作者：
Loda, Massimo
中科院分区：
文献类型：
--
作者：
Berger, Raanan;Lin, Douglas I.;Loda, Massimo
前列腺癌进展到对激素消融的抵抗状态的潜在机制仍然知之甚少。在这里，我们研究了雄激素受体（AR）和Her-2/neu在前列腺癌细胞之间的关系。Her-2/neu（c-ErbB 2）的过表达激活AR途径，并赋予前列腺癌细胞在雄激素缺乏环境中的生存和生长优势。在体外，雄激素的缺乏或All阻断诱导Her-2/neu蛋白表达和磷酸化。与此相反，在再给药雄激素，Her-2/neu mRNA，蛋白质和磷酸化水平线性下降，增加浓度的双氢睾酮作为LNCaP细胞重新进入细胞周期。在体内，在原位注射的LNCaP细胞中通过去势诱导Her-2/neu导致前列腺特异性抗原分泌到小鼠血清中的进行性增加，表明Her-2/neu介导的All依赖性转录在去势后发生并导致肿瘤细胞生长。最后，选择用AIR特异性短发夹RNA稳定转染的LNCaP细胞导致Her-2/neu过表达。类似地，Her-2/neu的敲低导致AR的诱导。然而，当同时靶向Her-2/neu和AR时，我们观察到细胞死亡，而存活的细胞保留Her-2/neu的低水平表达。因此，Her-2/neu的诱导和激活发生在雄激素耗尽的环境中或作为AR失活的结果，促进前列腺癌细胞的消融抗性存活。这些数据为靶向Her-2/neu治疗难治性前列腺癌提供了生物化学依据。
The mechanisms underlying the progression of prostate cancer to a state of resistance to hormone ablation remain poorly understood. Here, we have investigated the relationship between androgen receptor (AR) and Her-2/neu in prostate cancer cells. Overexpression of Her-2/neu (c-ErbB2) activates the AR pathway and confers a survival and growth advantage to prostate cancer cells in an androgen-deficient milieu. In vitro, the absence of androgens or All blockade induced Her-2/neu protein expression and phosphorylation. In contrast, upon readministration of androgens, Her-2/neu mRNA, protein, and phosphorylation levels decreased linearly with increasing concentrations of dihydrotestosterone as LNCaP cells reentered the cell cycle. In vivo, induction of Her-2/neu by castration in orthotopically injected LNCaP cells resulted in a progressive increase in prostate-specific antigen secretion into the mouse serum, indicating that Her-2/neumediated, All-dependent transcription occurs following castration and results in tumor cell growth. Finally, selection of LNCaP cells stably transfected with short hairpin RNA specific for AIR resulted in Her-2/neu overexpression. Similarly, knockdown of Her-2/neu led to induction of AR. However, when Her-2/neu and AR were simultaneously targeted, we observed cell death, whereas surviving cells retained low level expression of Her-2/neu. Thus, induction and activation of Her-2/neu occurs in an androgen-depleted environment or as a result of AR inactivation, promoting ablation-resistant survival of prostate cancer cells. These data provide the biochemical rationale to target Her-2/neu in hormone-refractory prostate cancer.