Expression of adrenomedullin and peptide amidation activity in human prostate cancer and in human prostate cancer cell lines.
Expression of adrenomedullin and peptide amidation activity in human prostate cancer and in human prostate cancer cell lines.
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发表时间：
2001-02
期刊：
影响因子：
11.2
通讯作者：
Palma Rocchi;Françoise Boudouresque;Alfredo J. Zamora;Xavier Muracciole;E. Lechevallier;Pierre-Marie Martin;L'Houcine Ouafik
中科院分区：
文献类型：
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作者：
Palma Rocchi;Françoise Boudouresque;Alfredo J. Zamora;Xavier Muracciole;E. Lechevallier;Pierre-Marie Martin;L'Houcine Ouafik
在治疗性激素剥夺后，前列腺癌（CaP）细胞通常通过不明确的机制发展雄激素非依赖性生长。前列腺癌中神经内分泌（NE）细胞的存在通常比正常前列腺中更多，并且NE细胞的频率与肿瘤恶性程度、雄激素敏感性丧失、自分泌-旁分泌活性增加和预后不良相关。在一些CaP中，神经肽先前被认为是生长因子。肽酰甘氨酸α-酰胺化单加氧酶（PAM）是从其无活性的甘氨酸延伸前体产生α-酰胺化生物活性肽的酶。在目前的工作中，我们证明，雄激素非依赖性PC-3和DU 145细胞系，来自人钙磷，表达PAM在体外和移植在无胸腺裸鼠，表明他们能够产生α-酰胺化肽。首先，在雄激素敏感的LNCaP细胞系中发现几乎检测不到PAM水平。我们还表明，而PC-3和DU 145细胞产生和分泌肾上腺髓质素（AM），一种多功能酰胺化肽，没有发现在LNCaP细胞的表达。我们进一步证明，AM作为DU 145细胞的生长因子，这表明存在自分泌环路机制，可能会驱动肿瘤生长。PAM mRNA水平被发现是3倍高，前列腺癌相比，人类良性前列腺增生（BPH）的实时定量逆转录-PCR证明。BPH和CaP中AM信息表达的分析（Gleason评分，6-9）显示良性和CaP之间的明显区别。仅在腺癌组织中检测到表达，在具有高Gleason评分的样品中显著增加。免疫细胞化学，AM定位于癌上皮隔室。NE表型，神经元特异性烯醇化酶（NSE）的免疫细胞化学定位后，被发现在上皮和间质室的癌症，在BPH，只有一些备用的基底细胞NSE标记。能够通过自分泌-旁分泌机制诱导雄激素非依赖性肿瘤生长的细胞群分泌的肽可以加速癌症进展。
After therapeutic hormone deprivation, prostate cancer (CaP) cells often develop androgen-independent growth through not-well-defined mechanisms. The presence of neuroendocrine (NE) cells is often greater in prostate carcinoma than in normal prostate, and the frequency of NE cells correlates with tumor malignancy, loss of androgen sensitivity, increase of autocrine-paracrine activity, and poor prognosis. In some CaPs, neuropeptides have been previously implicated as growth factors. Peptidylglycine alpha-amidating monooxygenase (PAM) is the enzyme producing alpha-amidated bioactive peptides from their inactive glycine-extended precursors. In the present work, we demonstrate that androgen-independent PC-3 and DU145 cell lines, derived from human CaP, express PAM in vitro and in xenografts implanted in athymic nude mice, indicating that they are able to produce alpha-amidated peptides. Contrarily, barely detectable levels of PAM were found in the androgen-sensitive LNCaP cell line. We also show that whereas PC-3 and DU145 cells produce and secrete adrenomedullin (AM), a multifunctional amidated peptide, no expression was found in LNCaP cells. We further demonstrate that AM acts as a growth factor for DU145 cells, which suggests the existence of an autocrine loop mechanism that could potentially drive neoplastic growth. PAM mRNA levels were found to be 3-fold higher in prostate adenocarcinomas compared with that of human benign prostate hyperplasia (BPH) as demonstrated by real-time quantitative reverse transcription-PCR. The analysis of AM message expression in BPH and CaP (Gleason's score, 6-9) shows a clear distinction between benign and CaP. The expression was detected only in adenocarcinomas tissues with a marked increase in samples with a high Gleason's score. Immunocytochemically, AM was localized in the carcinomatous epithelial compartment. NE phenotype, assessed after the immunocytochemical localization of neuron-specific enolase (NSE), was found in both the epithelial and the stromal compartments of cancers; in BPH, only some spare basal cells were NSE-labeled. Cancer progression could be accelerated by peptides secreted by a population of cells capable of inducing androgen-independent tumoral growth via autocrine-paracrine mechanisms.