Lemur Tyrosine Kinase 2, a novel target in prostate cancer therapy.
Lemur Tyrosine Kinase 2, a novel target in prostate cancer therapy.
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DOI：
10.18632/oncotarget.3899
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发表时间：
2015-06-10
期刊：
影响因子：
--
通讯作者：
Bradbury NA
中科院分区：
文献类型：
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作者：
Shah K;Bradbury NA
从早期形式的前列腺癌到去势抵抗疾病的进展与信号转导活性的增加有关。大多数去势抵抗性癌症持续表达雄激素受体（AR）以及雄激素依赖基因。AR不仅受其相关类固醇激素的调控，还受多种调控和信号分子的调控，包括几种激酶。我们评估了狐猴酪氨酸激酶2 （LMTK2）在调节AR活性中的作用，因为一些全基因组关联研究（GWAS）已经显示LMTK2活性与前列腺癌的发展有显著的关联。我们证实，前列腺癌组织中不仅LMTK2 mRNA减少，而且LMTK2蛋白水平也显著降低。在前列腺细胞系中敲低LMTK2蛋白可显著增加雄激素应答基因的转录。此外，LMTK2敲低导致LNCaP细胞中前列腺癌干细胞群增加，表明肿瘤致癌性增加。使用多种方法，我们还证明了LMTK2与AR相互作用，从而将LMTK2作为调节AR活动的信号复合物的组成部分。我们发现LMTK2是AR活性的负调节因子，这为去势抵抗性前列腺癌中AR应答基因的激活定义了一种新的细胞途径。此外，药理学操作LMTK2活性将为去势抵抗性前列腺癌患者提供更有效的治疗新靶点。
Progression from early forms of prostate cancer to castration-resistant disease is associated with an increase in signal transduction activity. The majority of castration-resistance cancers persist in the expression of the androgen receptor (AR), as well as androgen-dependent genes. The AR is regulated not only by it associated steroid hormone, but also by manifold regulatory and signaling molecules, including several kinases. We undertook evaluation of the role of Lemur Tyrosine Kinase 2 (LMTK2) in modulating AR activity, as several Genome Wide Association Studies (GWAS) have shown a marked association of LMTK2 activity with the development of prostate cancer. We confirm that not only is LMTK2 mRNA reduced in prostate cancer tissue, but also LMTK2 protein levels are markedly diminished. Knockdown of LMTK2 protein in prostate cell lines greatly increased the transcription of androgen-responsive genes. In addition, LMTK2 knockdown led to an increase in prostate cancer stem cell populations in LNCaP cells, indicative of increased tumorogenicity. Using multiple approaches, we also demonstrate that LMTK2 interacts with the AR, thus putting LMTK2 as a component of a signaling complex modulating AR activity. Our finding that LMTK2 is a negative regulator of AR activity defines a novel cellular pathway for activation of AR-responsive genes in castrate resistant-prostate cancer. Moreover, pharmacologic manipulation of LMTK2 activity will provide a novel therapeutic target for more effective treatments for patients with castrate-resistant prostate cancer.