Hypoxia inhibits expression of prolactin and secretion of cathepsin-D by the GH4C1 pituitary adenoma cell line
Hypoxia inhibits expression of prolactin and secretion of cathepsin-D by the GH4C1 pituitary adenoma cell line
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DOI：
10.1097/01.lab.0000098429.59348.36
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发表时间：
2003-11-01
影响因子：
5
通讯作者：
Clapp, C
中科院分区：
文献类型：
--
作者：
Cosío, G;Jeziorski, MC;Clapp, C
生长中的肿瘤内氧浓度的降低可能通过诱导血管生成因子的上调和抗血管生成剂的下调来刺激新血管形成。垂体腺瘤生长中的一个潜在重要分子是催乳素 (PRL)，它可以被组织蛋白酶-D 裂解，产生具有有效抗血管生成作用的 16-kDa 形式 (16K-PRL)。我们检测了培养的 GH4C1 垂体腺瘤细胞暴露于缺氧（0.1% 氧气）12 至 36 小时后 PRL 的表达。与缺氧细胞中血管生成因子血管内皮生长因子表达增加相反，缺氧条件下PRL mRNA以及细胞内和分泌的PRL水平显着降低。这种减少并不是由于转录或蛋白质合成的普遍抑制。尽管 16K-PRL 在生理 pH 条件下的条件培养基中并不明显，但降低 pH 以模拟酸性肿瘤微环境会导致 16K-PRL 的产生，而在从缺氧细胞中提取的培养基中，16K-PRL 急剧减少。 16K-PRL 的产生被组织蛋白酶-D 抑制剂胃酶抑素-A 阻断，缺氧条件培养基中 16K-PRL 形成的减少与组织蛋白酶-D 及其前体组织蛋白酶原-D 分泌的减少相关。因此，缺氧作用于 GH4C1 细胞，增加血管内皮生长因子表达，减少 PRL 合成，并通过抑制组织蛋白酶-D 蛋白水解来抑制 PRL 向 16K-PRL 的转化。这些机制可能协同作用，刺激泌乳素瘤中的血管生成。
Diminished oxygen concentration within growing tumors may stimulate neovascularization by inducing both up-regulation of angiogenic factors and down-regulation of antiangiogenic agents. A potentially important molecule in the growth of pituitary adenomas is prolactin (PRL), which can be cleaved by cathepsin-D to yield a 16-kDa form (16K-PRL) with potent antiangiogenic effects. We examined the expression of PRL in cultured GH4C1 pituitary adenoma cells after exposure to hypoxia (0.1 % oxygen) for periods of 12 to 36 hours. In contrast to increased expression of the angiogenic factor vascular endothelial growth factor in hypoxic cells, PRL mRNA and levels of intracellular and secreted PRL were significantly reduced under hypoxia. The reduction was not attributable to a general suppression of either transcription or protein synthesis. Although 16K-PRL was not evident in conditioned medium at physiologic pH, lowering the pH to mimic the acidic tumor microenvironment resulted in generation of 16K-PRL, which was sharply reduced in medium drawn from hypoxic cells. Production of 16K-PRL was blocked by the cathepsin-D inhibitor pepstatin-A, and the reduced 16K-PRL formation in hypoxic-conditioned medium correlated with a decrease in secretion of cathepsin-D and its precursor, procathepsin-D. Thus, hypoxia acts upon GH4C1 cells to increase vascular endothelial growth factor expression, decrease PRL synthesis, and suppress conversion of PRL to 16K-PRL via inhibition of cathepsin-D proteolysis. These mechanisms may act in concert to stimulate angiogenesis in prolactinomas.