Androgen-responsive and -unresponsive prostate cancer cell lines respond differently to stimuli inducing neuroendocrine differentiation
Androgen-responsive and -unresponsive prostate cancer cell lines respond differently to stimuli inducing neuroendocrine differentiation
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DOI：
10.1111/j.1365-2605.2009.01030.x
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发表时间：
2010-12-01
影响因子：
--
通讯作者：
Baldi, E.
中科院分区：
文献类型：
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作者：
Marchiani, S.;Tamburrino, L.;Baldi, E.
晚期前列腺癌(CAP)的雄激素剥夺治疗不可避免地使肿瘤去势抵抗和不治之症。在这种情况下，帽细胞发生神经内分泌分化(NED)，神经内分泌细胞释放的神经肽促进肿瘤进展。因此，在雄激素消融过程中，旨在预防或推迟NED的药物策略可以增加治疗的有效性。在CAP中诱发NED的机制和途径还知之甚少，而且数据往往不一致。在本研究中，我们使用了几种帽细胞系(雄激素反应型：LNCaP、PC3-AR、22Rv1和-不反应型：DU145和PC3)来评估雄激素剥夺或表皮生长因子(EGF)治疗后的NED。NED由神经元特异性烯醇化酶和嗜铬粒蛋白A的表达以及细胞的形态变化来确定。去雄激素诱导LNCaP和PC3-AR细胞发生NED，但不诱导22Rv1、PC3和DU145细胞发生NED。LNCaP和PC3-AR细胞也对thapsigargin诱导的细胞凋亡产生了抵抗力。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，表明无论NED诱导与否，雄激素受体表达都下调。用EGF处理DU145细胞可诱导NED，而EGF受体抑制剂gefinitib可阻止这一过程。反之，EGF对LNCaP和22Rv1细胞无明显影响。CAP细胞系对诱导NED的治疗没有明确的反应，这表明关于这个主题的研究应该在更能反映体内肿瘤变异性的广泛的细胞模型中进行。
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.