Endothelial p70 S6 kinase 1 in regulating tumor angiogenesis
Endothelial p70 S6 kinase 1 in regulating tumor angiogenesis
复制标题
内皮 p70 S6 激酶 1 调节肿瘤血管生成
DOI：
10.1158/0008-5472.can-08-0819
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发表时间：
2008-10-01
期刊：
影响因子：
11.2
通讯作者：
Jiang, Bing-Hua
中科院分区：
文献类型：
--
作者：
Liu, Ling-Zhi;Zheng, Jenny Z.;Jiang, Bing-Hua
p70 S6激酶1（p70 S6 K1）在响应生长因子和其他细胞信号调节蛋白质合成、细胞增殖、细胞周期进展和细胞存活方面发挥其功能。但p70 S6 K1在调节肿瘤生长和血管生成中的直接作用仍有待阐明。在这里，我们研究了p70 S6 K1在人真皮微血管内皮细胞（HDMEC）中表达的调节癌细胞诱导的肿瘤生长和血管生成的作用，发现HDMEC增强癌细胞诱导的肿瘤生长和血管生成。HDMECs中p70 S6 K1的组成性激活足以增强肿瘤生长和血管生成。在HDMECs中通过其显性阴性突变体抑制p70 S6 K1干扰肿瘤生长和血管生成，表明内皮细胞中的p70 S6 K1活性是调节肿瘤血管生成所必需的。我们发现p70 S6 K1调节人内皮细胞中缺氧诱导因子-1 α（HIF-1 α）的表达。内皮细胞中HIF-1 α的敲低降低了肿瘤生长和血管生成。这些结果表明p70 S6 K1和HIF-1在调节内皮功能以诱导肿瘤生长和血管生成中起重要作用。本研究有助于了解p70 S6 K1在调节血管生成和肿瘤生长中的作用和分子机制，以及内皮细胞p70 S6 K1/HIF-1信号通路在调节肿瘤微环境和血管生成中的作用。
The p70 S6 kinase 1 (p70S6K1) exerts its function in regulating protein synthesis, cell proliferation, cell cycle progression, and cell survival in response to growth factors and other cellular signals. But the direct effect of p70S6K1 in regulating tumor growth and angiogenesis remains to be elucidated. Here, we investigated the effect of p70S6K1 expressed in human dermal microvascular endothelial cells (HDMEC) in regulating cancer cell-inducing tumor growth and angiogenesis and found that HDMECs enhance cancer cell-induced tumor growth and angiogenesis. Constitutive activation of p70S6K1 in HDMECs is sufficient to enhance tumor growth and angiogenesis. Inhibition of p70S6K1 by its dominant-negative mutant in HDMECs interferes with tumor growth and angiogenesis, indicating that p70S6K1 activity in endothelial cells is required for regulating tumor angiogenesis. We found that p70S6K1 regulates hypoxia-inducible factor-1 alpha, (HIF-1 alpha) expression in the human endothelial cells. Knockdown of HIF-1 alpha in the endothelial cells decreases tumor growth and angiogenesis. These results show that p70S6K1 and HIF-1 play an important role in regulating the endothelial functions for inducing tumor growth and angiogenesis. This study helps to understand the role and molecular mechanism of p70S6K1 in regulating angiogenesis and tumor growth, and the role of endothelial p70S6K1/HIF-1 signaling in the regulation of tumor microenvironment and angiogenesis.