PI3K/PTEN/AKT signaling regulates prostate tumor angiogenesis
PI3K/PTEN/AKT signaling regulates prostate tumor angiogenesis
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DOI：
10.1016/j.cellsig.2007.07.025
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发表时间：
2007-12-01
影响因子：
4.8
通讯作者：
Jiang, Bing-Hua
中科院分区：
文献类型：
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作者：
Fang, Jing;Ding, Min;Jiang, Bing-Hua
PI3K通路通过其下游分子AKT发挥作用，调节细胞增殖、细胞转化、细胞凋亡、肿瘤生长和血管生成等多种细胞功能。 PTEN是PI3K的抑制剂，其缺失或突变在人类前列腺癌中很常见。但 PI3K/PTEN 信号在体内调节血管生成和肿瘤生长的直接作用和机制仍有待阐明。在本研究中，通过使用鸡绒毛尿囊膜 (CAM) 和裸鼠模型，我们证明 LY294002 抑制 PI3K 活性可减少 PC-3 细胞诱导的血管生成。 PC-3 细胞中 PI3K 的分子抑制剂 PTEN 的重建可抑制血管生成和肿瘤生长。免疫组织化学染色表明，PTEN 表达抑制肿瘤异种移植中 HIF-1 α、VEGF 和 PCNA 的表达。同样，AKT 显性失活突变体的表达也抑制血管生成和肿瘤生长，并降低肿瘤异种图中 HIF-1 α 和 VEGF 的表达。这些结果表明PTEN抑制PI3K信号通路可抑制肿瘤血管生成和肿瘤生长。此外，我们发现AKT是PI3K控制血管生成和肿瘤生长的下游靶标，PTEN可以通过激活PC-3细胞中的AKT来调节HIF-1的表达和VEGF的表达，从而抑制血管生成。 (C) 2007 Elsevier Inc. 保留所有权利。
PI3K pathway exerts its function through its downstream molecule AKT in regulating various cell functions including cell proliferation, cell transformation, cell apoptosis, tumor growth and angiogenesis. PTEN is an inhibitor of PI3K., and its loss or mutation is common in human prostate cancer. But the direct role and mechanism of PI3K/PTEN signaling in regulating angiogenesis and tumor growth in vivo remain to be elucidated. In this study, by using chicken chorioallantoic membrane (CAM) and in nude mice models, we demonstrated that inhibition of PI3K activity by LY294002 decreased PC-3 cells-induced angiogenesis. Reconstitution of PTEN, the molecular inhibitor of PI3K in PC-3 cells inhibited angiogenesis and tumor growth. Immunohistochemical staining indicated that PTEN expression suppressed HIF-1 alpha, VEGF and PCNA expression in the tumor xenographs. Similarly, expression of AKT dominant negative mutant also inhibited angiogenesis and tumor growth, and decreased the expression of HIF-1 alpha and VEGF in the tumor xenographs. These results suggest that inhibition of PI3K signaling pathway by PTEN inhibits tumor angiogenesis and tumor growth. In addition, we found that AKT is the downstream target of PI3K in controlling angiogenesis and tumor growth, and PTEN could inhibit angiogenesis by regulating the expression of HIF-1 and VEGF expression through AKT activation in PC-3 cells. (C) 2007 Elsevier Inc. All rights reserved.