Androgen receptor cross-talk with cell signalling pathways
Androgen receptor cross-talk with cell signalling pathways
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DOI：
10.1080/08977190412331279908
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发表时间：
2004-09-01
期刊：
影响因子：
1.8
通讯作者：
Culig, Z
中科院分区：
文献类型：
--
作者：
Culig, Z
雄激素受体（AR）参与晚期前列腺癌细胞事件的调节。它在原发性肿瘤中表达，也在内分泌治疗失败的患者转移瘤中表达。转移性肿瘤中AR的激活是由于受体的敏感性增加，点突变改变了激活谱，以及对各种非甾体化合物的反应。激活丝裂原活化蛋白激酶（MAPK）信号通路的肽生长因子以不依赖配体或协同的方式刺激AR活性。非甾体激活的结果取决于细胞和启动子的背景。Her-2/neu激活AR与LAPC-4异种移植物的肿瘤生长增强有关。MAPK或参与生长因子信号传导的蛋白激酶Akt是否直接磷酸化AR是一个有争议的问题。蛋白激酶A激活剂的AR配体依赖性激活也得到了证实。在生理条件下，低剂量雄激素增强AR活性可能对接受内分泌治疗的前列腺癌患者有重要意义。白细胞介素-6 （IL-6）和相关细胞因子也以不依赖配体的协同方式激活AR。IL-6是一种多效性的垂体生长调节剂，在一些前列腺癌中作为旁分泌生长抑制剂，在其他情况下作为自分泌生长刺激剂。IL-6激活AR需要Janus激酶/信号转导以及转录因子和MAPK的激活因子的功能途径。对参与配体非依赖性激活的AR共激活剂的研究可能会进一步提高对信号通路间串扰的理解。
The androgen receptor (AR) is implicated in regulation of cellular events in advanced prostate cancer. It is expressed in primary tumours as well as in metastases from patients who failed endocrine therapy. Activation of the AR in metastatic tumours occurs as a result of increased sensitivity of the receptor, point mutations that alter activation spectrum and in response to various nonsteroidal compounds. Peptide growth factors that activate the signalling pathway of mitogen-activated protein kinases (MAPK) stimulate AR activity in ligand-independent or synergistic manner. Outcome of nonsteroidal activation depends on cellular and promoter context. AR activation by Her-2/neu is associated with enhanced tumour growth of the LAPC-4 xenograft. The issue whether MAPK or protein kinase Akt involved in growth factor signalling directly phosphorylate the AR is a matter of debate. AR ligandin-dependent activation by protein kinase A activators was also demonstrated. Under physiological conditions, potentiation of AR activity by low doses of androgen might be of importance in prostate cancer patients who receive endocrine therapy. Interleukin-6 (IL-6) and related cytokines also activate AR in a ligand-independent and synergistic manner. IL-6 is a pleiotropic regulator of turnout growth, which in some prostate cancers acts as a paracrine growth inhibitor and in other cases as an autocrine growth stimulator. Activation of the AR by IL-6 requires functional pathways of Janus kinases/signal transducers and activators of transcription factors and MAPK. Studies on AR co-activators implicated in ligand-independent activation may further improve understanding of cross-talk between signalling pathways.