Adrenomedullin, an autocrine/paracrine factor induced by androgen withdrawal, stimulates 'neuroendocrine phenotype' in LNCaP prostate tumor cells
Adrenomedullin, an autocrine/paracrine factor induced by androgen withdrawal, stimulates 'neuroendocrine phenotype' in LNCaP prostate tumor cells
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DOI：
10.1038/sj.onc.1210656
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发表时间：
2008-01-17
期刊：
影响因子：
8
通讯作者：
Ouafik, L'Houcine
中科院分区：
文献类型：
--
作者：
Berenguer, C.;Boudouresque, F.;Ouafik, L'Houcine
前列腺癌(CAP)的神经内分泌(NE)分化被认为是雄激素非依赖性发生的早期标志。CAP获得NE属性的机制还知之甚少。本研究探讨了肾上腺髓质素(AM)在NE分化中的作用。实验干预雄激素状态后，观察AM和AM受体(降钙素受体样受体(CRLR)/受体活性修饰蛋白-2和3(RAMP2和RAMP3)的表达。去雄激素后，雄激素敏感型LNCaP细胞和去势后LNCaP异种移植动物的AM mRNA和免疫活性AM(ir-AM)水平分别增加4~7倍。用雄激素类似物(双氢睾酮；10(-9)M)处理LNCaP细胞可阻止AM mRNA和ir-AM水平的增加。有趣的是，CRLR、RAMP2和RAMP3的表达不受雄激素状态的调节。我们证明，在有血清存在的情况下，AM能够通过CRLR/RAMP2和RAMP3诱导LNCaP细胞的NE表型，包括延长神经突起和表达神经元特异烯醇化酶(NSE)，以剂量依赖的方式产生cGMP，这是由百日咳毒素敏感的GTP结合蛋白介导的。8-bromo-cGMP模拟AM对细胞分化的影响。我们证明AM诱导G-激酶Iα易位到细胞核。蛋白激酶G抑制剂KT-5823可抑制AM和8-bromo-cGMP诱导的轴突生长。在未去势的动物中，AM可增强LNCaP移植瘤中NSE和嗜铬粒蛋白A的表达，并显著提高血清NSE水平，而对肿瘤生长无影响。在去势动物中，腹腔注射AM的结果是240+/-18%(P
Neuroendocrine (NE) differentiation in prostate cancer (CaP) has been reported to be an early marker associated with the development of androgen independence. The mechanisms by which CaP acquires NE properties are poorly understood. In this study, a putative role of adrenomedullin (AM) in the NE differentiation was investigated. The expression of AM and AM receptors (calcitonin receptor-like receptor (CRLR)/receptor activity modifying protein-2 and -3 (RAMP2 and RAMP3) was evaluated after experimental manipulation of androgen status. Levels of AM mRNA and immunoreactive AM (ir-AM) increased four-to sevenfold in androgen-sensitive LNCaP cells after androgen withdrawal in vitro and in LNCaP xenograftsin animals after castration. Treatment of LNCaP cells with androgen analogue (dihydrotestosterone; 10(-9) M) prevented the increase in AM mRNA and ir-AM levels. Interestingly, the expression of CRLR, RAMP2 and RAMP3 is not regulated by androgen status. We demonstrate that in the presence of serum, AM is able to induce an NE phenotype in LNCaP cells via CRLR/ RAMP2 and RAMP3, which includes extension of neuritic processes and expression of the neuron-specific enolase (NSE), producing cGMP in a dose-dependent manner, which is mediated by a pertussis toxin-sensitive GTP-binding protein. 8-bromo-cGMP mimicked the effects of AM on cell differentiation. We demonstrate that AM induces a G-kinase I alpha translocation to the nucleus. The protein kinase G inhibitor KT-5823 inhibited the neurite outgrowth induced by both AM and 8-bromo-cGMP. In noncastrated animals, administration of AM enhanced expression of NSE and chromogranin A in LNCaP xenografts with a significant increase of NSE levels in serum and no changes in tumor growth. In castrated animals, intraperitoneal injection of AM resulted in a 240 +/- 18% ( P