Conditional Akt activation promotes androgen-independent progression of prostate cancer
Conditional Akt activation promotes androgen-independent progression of prostate cancer
复制标题
有条件的 Akt 激活可促进前列腺癌的雄激素非依赖性进展。
DOI：
10.1093/carcin/bgl193
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发表时间：
2007-03-01
期刊：
影响因子：
4.7
通讯作者：
Spencer, David
中科院分区：
文献类型：
--
作者：
Li, Benyi;Sun, Aijing;Spencer, David
侵袭性雄激素非依赖性（也称为难治性）前列腺癌是一个主要的临床障碍，因为没有治愈的方法。先前的研究表明Akt激活与前列腺癌从雄激素依赖性发展到雄激素非依赖性阶段有关。然而，它在这一过程中的因果作用尚未确定。主要的限制之一是缺乏一个良好控制的诱导系统来研究Akt参与。最近，我们开发了一种新的诱导型Akt（iAKT）系统的基础上化学诱导二聚化（CID）的方法。该系统允许在生理环境中有条件地激活Akt。利用这种iAKT系统，我们发现Akt激活防止血清撤除后的细胞死亡，并在体外不存在雄激素的情况下促进人前列腺癌LNCaP细胞的细胞增殖，该细胞在雄激素撤除后应停止生长，甚至在血清饥饿后死亡。使用在前列腺上皮中有条件地表达iAKT系统的转基因小鼠模型，在体内进一步证明了iAKT诱导的死亡保护和生长促进。最重要的是，在源自LNCaP细胞的小鼠异种移植模型中，iAKT活化通过增强细胞增殖和抑制细胞凋亡促进去势动物中的肿瘤生长。综上所述，我们的数据表明Akt激活在前列腺癌雄激素非依赖性进展中起着致病作用。这项研究提供了Akt靶向治疗难治性前列腺癌的重要相关性。
Aggressive androgen-independent (also termed as hormone-refractory) prostate cancer is a major clinical obstacle because there is no means to cure. Previous studies have shown that Akt activation is associated with prostate cancer progression from androgen-dependent to androgen-independent stage. However, its causative role in this process has not been established. One of the major limitations is the lack of a well-controlled inducible system to study Akt involvement. Recently, we developed a novel inducible Akt (iAKT) system based on a chemically induced dimerization (CID) approach. This system allows for conditional activation of Akt in a physiological setting. Utilizing this iAKT system, we found that Akt activation prevented cell death after serum withdrawal and promoted cell proliferation in the absence of androgen in vitro in human prostate cancer LNCaP cells, which should stop growing after androgen withdrawal or even die after serum starvation. The iAKT-induced death protection and growth promotion were further demonstrated in vivo using a transgenic mouse model that expresses the iAKT system conditionally in the prostate epithelium. Most importantly, in a mouse xenograft model derived from LNCaP cells, iAKT activation promoted tumor growth in castrated animals by enhancing cell proliferation and inhibiting apoptosis. Taken together, our data suggest that Akt activation is playing a causative role in androgen-independent progression of prostate cancer. This study provides a significant relevance of Akt-targeted therapy for hormone-refractory prostate cancers.