P2-PURINERGIC RECEPTOR AGONISTS INHIBIT THE GROWTH OF ANDROGEN-INDEPENDENT PROSTATE CARCINOMA-CELLS
P2-PURINERGIC RECEPTOR AGONISTS INHIBIT THE GROWTH OF ANDROGEN-INDEPENDENT PROSTATE CARCINOMA-CELLS
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DOI：
10.1172/jci115562
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发表时间：
1992-01-01
影响因子：
15.9
通讯作者：
TREPEL, JB
中科院分区：
文献类型：
--
作者：
FANG, WG;PIRNIA, F;TREPEL, JB
为了开发治疗晚期激素难治性前列腺癌的新方法，研究了调节人雄激素非依赖性前列腺癌细胞系生长的信号转导。激动剂刺激的 Ca2+ 动员是其他分泌细胞类型中的一个关键调节事件，被研究作为鉴定先前未描述的可能转导生长抑制信号的质膜受体的一种手段。在所有测试的细胞系中，P2-嘌呤能受体激动剂，包括 ATP 和某些抗水解腺嘌呤核苷酸，诱导细胞质游离 Ca2+ 快速、瞬时增加，在 50 至 100 nM ATP 时可检测到，在 100-mu-M ATP 时达到最大，并被细胞外 Ca2+ 螯合抑制约 50%。添加后8秒内，ATP刺激多磷脂酰肌醇产物肌醇(1,4,5)三磷酸、肌醇(1,3,4)三磷酸和肌醇四磷酸的积累。除了刺激磷脂酰肌醇周转和 Ca2+ 动员之外，ATP 和抗水解 ATP 类似物还诱导所有测试品系的生长抑制 > 90%。这些数据表明，人雄激素非依赖性前列腺癌细胞表达与磷脂酶 C 相关的功能性 P2 嘌呤能受体，并且该受体的激动剂具有明显的生长抑制作用，这表明对这种常见成人肿瘤有一种新的治疗方法。
To develop a new approach to the treatment of advanced, hormone-refractory prostate cancer, the signal transductions regulating the growth of human androgen-independent prostate carcinoma cell lines were studied. Agonist-stimulated Ca2+ mobilization, a critical regulatory event in other secretory cell types, was studied as a means of identifying previously undescribed plasma membrane receptors that may transduce a growth inhibitory signal. In all of the cell lines tested, P2-purinergic receptor agonists, including ATP and certain hydrolysis-resistant adenine nucleotides, induced a rapid, transient increase in cytoplasmic free Ca2+ that was detectable at 50 to 100 nM ATP, was maximal at 100-mu-M ATP, and was inhibited approximately 50% by chelation of extracellular Ca2+. Within 8 s after addition, ATP stimulated accumulation of the polyphosphatidylinositol products inositol (1, 4, 5) trisphosphate, inositol (1, 3, 4) trisphosphate, and inositol tetrakisphosphate. In addition to stimulating phosphatidylinositol turnover and Ca2+ mobilization, ATP and hydrolysis-resistant ATP analogues induced > 90% inhibition of the growth of all lines tested. These data demonstrate that human androgen-independent prostate carcinoma cells express functional P2-purinergic receptors linked to phospholipase C, and that agonists of this receptor are markedly growth inhibitory, suggesting a novel therapeutic approach to this common adult neoplasm.