DNA licensing as a novel androgen receptor mediated therapeutic target for prostate cancer.
DNA licensing as a novel androgen receptor mediated therapeutic target for prostate cancer.
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DOI：
10.1677/erc-08-0205
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发表时间：
2009-06
影响因子：
3.9
通讯作者：
Isaacs JT
中科院分区：
文献类型：
--
作者：
D'Antonio JM;Vander Griend DJ;Isaacs JT
在细胞周期的G1中期，复制起点协调复制前复合物（pre-RC）的有序组装，允许DNA复制所需的DNA许可。前RC的细胞周期蛋白依赖性激酶激活促进了额外信号传导因子的募集，这触发了DNA解旋和复制，同时将这种DNA复制限制为每个细胞周期一次且仅一次。对于正常和恶性前列腺，雄激素是细胞增殖和DNA复制的主要刺激物。在这两种情况下，都需要雄激素与雄激素受体（AR）结合。然而，这种AR刺激的细胞增殖和DNA合成中涉及的生化级联反应在正常前列腺细胞与恶性前列腺细胞中是显著不同的。在正常前列腺中，AR刺激的基质细胞旁分泌雄激素刺激前列腺上皮细胞内的DNA复制，其中AR作为肿瘤抑制基因通过诱导增殖静止和终末分化发挥作用。通过直接对比，前列腺癌细胞中的核AR通过将AR并入前RC自主刺激连续生长。表达AR的前列腺癌细胞的这种功能增益要求AR在有丝分裂期间被有效降解，因为缺乏这种降解导致重新许可问题，导致在随后的细胞周期期间的S期停滞。因此，获得AR作为DNA复制许可复合物的一部分，代表了我们如何看待AR在前列腺癌生物学中的作用的范式转变，并在AR表达的前列腺癌细胞中引入了一种新的脆弱性，易于进行治疗干预。
During middle G1 of the cell cycle origins of replication orchestrate the ordered assembly of the pre-replication complex (pre-RC), allowing licensing of DNA required for DNA replication. Cyclin-dependent kinase activation of the pre-RC facilitates the recruitment of additional signaling factors, which triggers DNA unwinding and replication, while limiting such DNA replication to once and only once per cell cycle. For both the normal and malignant prostate, androgen is the major stimulator of cell proliferation and thus DNA replication. In both cases, the binding of androgen to the androgen receptor (AR) is required. However, the biochemical cascade involved in such AR-stimulated cell proliferation and DNA synthesis is dramatically different in normal versus malignant prostate cells. In normal prostate, AR-stimulated stromal cell paracrine secretion of andromedins stimulates DNA replication within prostatic epithelial cells, in which AR functions as a tumor suppressor gene by inducing proliferative quiescence and terminal differentiation. By direct contrast, nuclear AR in prostate cancer cells autonomously stimulates continuous growth via incorporation of AR into the pre-RC. Such a gain of function by AR-expressing prostate cancer cells requires that AR be efficiently degraded during mitosis since lack of such degradation leads to re-licensing problems, resulting in S-phase arrest during the subsequent cell cycle. Thus, acquisition of AR as part of the licensing complex for DNA replication represents a paradigm shift in how we view the role of AR in prostate cancer biology, and introduces a novel vulnerability in AR-expressing prostate cancer cells apt for therapeutic intervention.