Marchiani S, Tamburrino L, Nesi G, Paglierani M, Gelmini S, Orlando C, Maggi M, Forti G, Baldi E
Department of Clinical Physiopathology: Andrology, University of Florence, Florence, Italy.
Int J Androl. 2010 Dec;33(6):784-93. doi: 10.1111/j.1365-2605.2009.01030.x.
The treatment of advanced prostate cancer (CaP) with androgen deprivation therapy inevitably renders the tumours castration resistant and incurable. Under these conditions, neuroendocrine differentiation (NED) of CaP cells occurs and neuropeptides released by neuroendocrine cells facilitate tumour progression. Pharmacological strategies aiming to prevent or delay NED during androgen ablation could, therefore, increase the effectiveness of the therapy. Mechanisms and pathways inducing NED in CaP are poorly understood and data are often discordant. In the present study, we used several CaP cell lines (androgen-responsive: LNCaP, PC3-AR, 22RV1 and -irresponsive: DU145 and PC3) to evaluate NED after androgen deprivation or treatment with epidermal growth factor (EGF). NED was determined by neuron-specific enolase and chromogranin A expression and by the occurrence of morphological changes in the cells. Androgen-deprivation conditions induced NED in LNCaP and PC3-AR, but not in 22Rv1, PC3 and DU145 cells. LNCaP and PC3-AR cells also became resistant to thapsigargin-induced apoptosis. In all the AR-positive cell lines, androgen deprivation caused a decrease in androgen receptor expression indicating that it is downregulated irrespective of NED induction. Treatment with EGF induced NED in DU145 cells and the EGF receptor inhibitor gefinitib prevented the process. On the contrary, no effect of EGF was demonstrated in LNCaP or 22Rv1 cells. CaP cell lines did not respond univocally to treatments inducing NED, suggesting that studies on this topic should be performed in a wide spectrum of cell models which can be more indicative of the tumour variability in vivo.
采用雄激素剥夺疗法治疗晚期前列腺癌（CaP）不可避免地会使肿瘤产生去势抵抗且无法治愈。在这些情况下，CaP细胞会发生神经内分泌分化（NED），神经内分泌细胞释放的神经肽会促进肿瘤进展。因此，旨在预防或延缓雄激素消融过程中NED的药理学策略可能会提高治疗效果。目前，CaP中诱导NED的机制和途径尚不清楚，数据也常常不一致。在本研究中，我们使用了几种CaP细胞系（雄激素反应性：LNCaP、PC3-AR、22RV1；非反应性：DU145和PC3）来评估雄激素剥夺或表皮生长因子（EGF）处理后的NED。通过神经元特异性烯醇化酶和嗜铬粒蛋白A的表达以及细胞形态变化来确定NED。雄激素剥夺条件在LNCaP和PC3-AR细胞中诱导了NED，但在22Rv1、PC3和DU145细胞中未诱导。LNCaP和PC3-AR细胞对毒胡萝卜素诱导的凋亡也产生了抗性。在所有AR阳性细胞系中，雄激素剥夺导致雄激素受体表达下降，这表明无论是否诱导NED，雄激素受体都会下调。EGF处理在DU145细胞中诱导了NED，而EGF受体抑制剂吉非替尼可阻止这一过程。相反，在LNCaP或22Rv1细胞中未显示出EGF的作用。CaP细胞系对诱导NED的处理反应并不一致，这表明关于该主题的研究应在更能反映体内肿瘤变异性的广泛细胞模型中进行。
