PTEN and phosphatidylinositol 3'-kinase inhibitors up-regulate p53 and block tumor-induced angiogenesis: evidence for an effect on the tumor and endothelial compartment.
PTEN and phosphatidylinositol 3'-kinase inhibitors up-regulate p53 and block tumor-induced angiogenesis: evidence for an effect on the tumor and endothelial compartment.
复制标题
DOI：
--
复制
发表时间：
2003-07
期刊：
影响因子：
11.2
通讯作者：
J. Su;L. Mayo;D. Donner;D. Durden
中科院分区：
文献类型：
--
作者：
J. Su;L. Mayo;D. Donner;D. Durden
我们实验室的前期工作表明，在恶性胶质瘤中，PTEN调节肿瘤诱导的血管生成和血小板反应蛋白1的表达。在此，我们首次证明了全身给予磷脂酰肌醇3 '-激酶（PI 3 K）抑制剂（LY 294002）在体内具有抗肿瘤和抗血管生成活性。我们发现，在胶质瘤细胞中，PTEN重建减少了AKT的磷酸化，诱导了p53的反式激活（7.5倍诱导），并增加了p53靶基因，p21（waf-1）和胰岛素样生长因子结合蛋白3的表达。PTEN和LY 294002在人脑内皮细胞中诱导p53活性，表明PTEN和PI 3 K通路可以通过直接作用于肿瘤和内皮细胞来抑制癌症的进展。在异位皮肤和原位脑肿瘤模型中测试了PTEN和LY 294002抑制U87 MG或U373 MG神经胶质瘤生长的能力。LY 294002在体内可抑制胶质瘤生长，诱导肿瘤消退，降低脑肿瘤发生率，并阻断U87 MG细胞体内肿瘤诱导的血管生成反应。这些数据提供了证据表明，PTEN和PI 3 K抑制剂都调节p53功能，并显示出体内抗血管生成和抗肿瘤活性。这些结果提供了证据表明，两个肿瘤抑制基因，PTEN和p53，共同作用，以阻止体内肿瘤的进展。我们的数据为LY 294002治疗恶性胶质瘤的体内疗效提供了第一个临床前证据。
Previous work from our laboratory demonstrated that PTEN regulates tumor-induced angiogenesis and thrombospondin 1 expression in malignant glioma. Herein, we demonstrated the first evidence that the systemic administration of a phosphatidylinositol 3'-kinase (PI3K) inhibitor (LY294002) has antitumor and antiangiogenic activity in vivo. We show that PTEN reconstitution diminished phosphorylation of AKT, induced the transactivation of p53 (7.5-fold induction) and increased the expression of p53 target genes, p21(waf-1) and insulin-like growth factor binding protein 3 in glioma cells. PTEN and LY294002 induced p53 activity in human brain endothelial cells, suggesting that PTEN and PI3K pathways can suppress the progression of cancer through direct actions on tumor and endothelial cells. The capacity of PTEN and LY294002 to inhibit U87MG or U373MG glioma growth was tested in an ectopic skin and orthotopic brain tumor model. LY294002 inhibited glioma tumor growth in vivo, induced tumor regression, decreased the incidence of brain tumors, and blocked the tumor-induced angiogenic response of U87MG cells in vivo. These data provide evidence that both PTEN and PI3K inhibitors regulate p53 function and display in vivo antiangiogenic and antitumor activity. These results provide evidence that the two tumor suppressor genes, PTEN and p53, act together to block tumor progression in vivo. Our data provide the first preclinical evidence for the in vivo efficacy for LY294002 in the treatment of malignant gliomas.