Inhibition of the phosphatidylinositol 3-kinase/Akt pathway by inositol pentakisphosphate results in antiangiogenic and antitumor effects
Inhibition of the phosphatidylinositol 3-kinase/Akt pathway by inositol pentakisphosphate results in antiangiogenic and antitumor effects
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DOI：
10.1158/0008-5472.can-05-0121
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发表时间：
2005-09-15
期刊：
影响因子：
11.2
通讯作者：
Falasca, M
中科院分区：
文献类型：
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作者：
Maffucci, T;Piccolo, E;Falasca, M
本研究的目的是研究最近鉴定的磷脂酰肌醇3-激酶（PI 3 K）/Akt抑制剂肌醇（1，3，4，5，6）五磷酸[Ins（1，3，4，5，6）P-5]的抗血管生成和体内性质。由于PI 3 K/Akt通路的激活是导致血管生成的一些事件中的关键步骤，因此在体外在人脐静脉内皮细胞（HUVEC）中测试了Ins（1，3，4，5，6）P-5对碱性成纤维细胞生长因子（FGF-2）诱导的Akt磷酸化、细胞存活、运动性和小管形成的影响。采用皮下注射法评价Ins（1，3，4，5，6）P5对FGF-2诱导的体内血管生成的影响。植入Matrigel。此外，还观察了Ins（1，3，4，5，6）P-5对卵巢癌SKOV-3移植瘤生长的影响。在这里，我们表明，FGF-2诱导Akt磷酸化的HUVEC导致抗凋亡作用，在血清剥夺细胞和细胞运动的增加。Ins（1，3，4，5，6）P-5阻断FGF-2介导的Akt磷酸化并抑制HUVEC的存活和迁移。Ins（1，3，4，5，6）P-5抑制FGF-2诱导的HUVEC毛细血管形成，抑制FGF-2诱导的血管生成反应。最后，Ins（1，3，4，5，6）P-5阻断s.c. SKOV-3在裸鼠中异种移植物的生长与顺铂相同的程度，并且它完全抑制体内Akt磷酸化。这些数据明确鉴定Akt抑制剂Ins（1，3，4，5，6）P-5作为特异性抗血管生成和抗肿瘤因子。PI 3 K/Akt通路的不适当激活与包括癌症在内的几种疾病的发展有关，使该通路成为治疗策略的有吸引力的靶标。在这方面，Ins（I，3，4，5，6）P-5，一种具有特定促凋亡和抗血管生成特性的水溶性天然化合物，可能会导致成功的抗癌治疗策略。
The purpose of this study was to investigate the antiangiogenic and in vivo properties of the recently identified phosphatidylinositol 3-kinase (PI3K)/Akt inhibitor Inositol(1,3,4,5,6) pentakisphosphate [Ins(1,3,4,5,6)P-5]. Because activation of the PI3K/Akt pathway is a crucial step in some of the events leading to angiogenesis, the effect of Ins(1,3,4,5,6)P-5 on basic fibroblast growth factor (FGF-2)induced Akt phosphorylation, cell survival, motility, and tubulogenesis in vitro was tested in human umbilical vein endothelial cells (HUVEC). The effect of Ins(1,3,4,5,6)P5 on FGF-2-induced angiogenesis in vivo was evaluated using s.c. implanted Matrigel in mice. In addition, the effect of Ins(1,3,4,5,6)P-5 on growth of ovarian carcinoma SKOV-3 xenograft was tested. Here, we show that FGF-2 induces Akt phosphorylation in HUVEC resulting in antiapoptotic effect in serum-deprived cells and increase in cellular motility. Ins(1,3,4,5,6)P-5 blocks FGF-2-mediated Akt phosphorylation and inhibits both survival and migration in HUVEC. Moreover, Ins(1,3,4,5,6)P-5 inhibits the FGF-2-mediated capillary tube formation of HUVEC plated on Matrigel and the FGF-2-induced angiogenic reaction in BALB/c mice. Finally, Ins(1,3,4,5,6)P-5 blocks the s.c. growth of SKOV-3 xenografted in nude mice to the same extent than cisplatin and it completely inhibits Akt phosphorylation in vivo. These data definitively identify the Akt inhibitor Ins(1,3,4,5,6)P-5 as a specific antiangiogenic and antitumor factor. Inappropriate activation of the PI3K/Akt pathway has been linked to the development of several diseases, including cancer, making this pathway an attractive target for therapeutic strategies. In this respect, Ins(I,3,4,5,6)P-5, a water-soluble, natural compound with specific proapoptotic and antiangiogenic properties, might result in successful anticancer therapeutic strategies.