TERMINAL NEUROENDOCRINE DIFFERENTIATION OF HUMAN PROSTATE CARCINOMA-CELLS IN RESPONSE TO INCREASED INTRACELLULAR CYCLIC-AMP
TERMINAL NEUROENDOCRINE DIFFERENTIATION OF HUMAN PROSTATE CARCINOMA-CELLS IN RESPONSE TO INCREASED INTRACELLULAR CYCLIC-AMP
复制标题
DOI：
10.1073/pnas.91.12.5330
复制
发表时间：
1994-06-07
影响因子：
11.1
通讯作者：
TREPEL, JB
中科院分区：
文献类型：
--
作者：
BANG, YJ;PIRNIA, F;TREPEL, JB
最近的临床病理研究表明，许多前列腺癌表现出局灶性神经内分泌分化，而神经内分泌分化在晚期间变性肿瘤中最为明显。在研究人前列腺癌细胞系中的生长调节信号转导事件时，我们发现在四个细胞系中的两个，雄激素敏感株LNCaP和高度转移的雄激素非依赖性株PC-3-M中，通过加入cAMP类似物或磷酸二酯酶抑制剂而升高的cAMP诱导了明显的神经元形态。超微结构分析显示，cAMP诱导LNCaP细胞出现神经分泌细胞样致密核颗粒。对未经处理的LNCaP和PC 3-M细胞的表型分析表明，这两个细胞系都表达神经峰标志物S-100、嗜铬粒蛋白A、pp60(c-src)和神经元特异性烯醇化酶，以及上皮标志物Ks1/4和阶段特异性胚胎抗原4。在PC-3-M Tell细胞中，cAMP显著上调神经元特异性烯醇化酶蛋白，并导致神经内分泌标志物pp60(c-src)比活性增加，KS1/4和阶段特异性胚胎抗原4的表达下调。除了对谱系标记的影响外，cAMP处理还诱导了G(1)同步化、生长停滞和克隆形成能力的丧失，表明终末分化。我们的数据提供了前列腺癌家族承诺可塑性的直接证据。我们已经证明，细胞内cAMP类似物可以诱导终末分化，这表明耐水解环核苷酸可能为晚期前列腺癌的治疗提供了另一种方法。
Recent clinicopathologic studies have shown that many prostatic adenocarcinomas express focal neuroendocrine differentiation and that neuroendocrine differentiation is most apparent in advanced anaplastic tumors. While studying growth-regulatory signal transduction events in human prostate carcinoma cell lines, we found that in two of four cell lines, the androgen-sensitive line LNCaP and the highly metastatic androgen-independent line PC-3-M, elevation of cAMP through addition of cAMP analogues or phosphodiesterase inhibitors induced a markedly neuronal morphology. Also in LNCaP cells ultrastructural analysis showed that cAMP induced the appearance of neurosecretory cell-like dense-core granules. Phenotypic analysis of untreated LNCaP and PC 3-M cells showed that both cell lines express markers of the neural crest including S-100, chromogranin A, pp60(c-src), and neuron-specific enolase as well as the epithelial marker KS1/4 and stage-specific embryonic antigen 4. In PC-3-M tells, cAMP markedly elevated neuron-specific enolase protein and caused an increase in the specific activity of the neuroendocrine marker pp60(c-src), and in both cell lines expression of KS1/4 and stage specific embryonic antigen 4 was down-regulated. In addition to effects on lineage markers, cAMP treatment induced G(1) synchronization, growth arrest, and loss of clonogenicity, indicating terminal differentiation. Our data provide direct evidence of plasticity in the lineage commitment of adenocarcinoma of the prostate. We have shown that cell-permeant cAMP analogues can induce terminal differentiation, suggesting that hydrolysis-resistant cyclic nucleotides may present an additional approach to the treatment of advanced prostate cancer.