A specific function for phosphatidylinositol 3-kinase α (p85α-p110α) in cell survival and for phosphatidylinositol 3-kinase β (p85α-p110β) in de novo DNA synthesis of human colon carcinoma cells
A specific function for phosphatidylinositol 3-kinase α (p85α-p110α) in cell survival and for phosphatidylinositol 3-kinase β (p85α-p110β) in de novo DNA synthesis of human colon carcinoma cells
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DOI：
10.1038/sj.onc.1203871
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发表时间：
2000-10-19
期刊：
影响因子：
8
通讯作者：
Roche, S
中科院分区：
文献类型：
--
作者：
Bénistant, C;Chapuis, H;Roche, S
我们之前已经证明了磷脂酰肌醇3-激酶(PI3K) α (p85 α -p110 α)和PI3K β (p85 α -p110 β)在非转化成纤维细胞中由各种有丝分裂原诱导的DNA合成中的重要功能，现在我们报告了这些酶在人类结肠癌细胞生长中的特殊作用。使用p110 α和p110 β催化亚基特异性抗体，PI3K α和PI3K β活性增加，在15/19的人类肿瘤活检中检测到相对于邻近的人类结肠和膀胱正常粘膜。与未转化成纤维细胞相比，在腺癌细胞系CaCo2、CO115、HCT 116、LS 174T和WiDr中也观察到这种活性的增加。在LS 174T细胞中观察到最大的PI3K α活性，在WiDr细胞中观察到最大的PI3K β活性。这与一些原发性肿瘤和已建立的细胞系中p110 α和p110 β蛋白水平的增加部分相关，表明PI3K的过表达与酶的失调有关。通过显微注射方法评估了这种激活的功能后果。在WiDr、HCT116和CO 115细胞中注射p110 β特异性中和抗体可抑制DNA的新生合成，而p110 γ特异性抗体则没有作用。中和p110 α特异性抗体诱导细胞凋亡，用caspase抑制剂z-VAD-fmk处理细胞可以恢复这种反应。我们得出结论，PI3K α和PI3K β在人类结肠癌细胞生长中发挥重要作用，PI3K β在新生DNA合成中具有特定功能，PI3K α参与细胞存活。
We have previously shown an important function of phosphatidylinositol 3-kinase (PI3K)alpha(p85 alpha-p110 alpha) and PI3K beta (p85-alpha-p110 beta) for DNA synthesis induced by various mitogens in non transformed fibroblasts and we now report a specific role of these enzymes in human colon cancer cell growth. Using antibodies specific to p110 alpha and to p110 beta catalytic subunits, increase in PI3K alpha and PI3K beta activities,vas detected in 15/19 human tumour biopsies relative to adjacent normal mucosa of human colon and bladder. Increase in such activities was also observed in adenocarcinoma cell lines CaCo2, CO115, HCT 116, LS 174T and WiDr relative to nontransformed fibroblasts. Maximal PI3K alpha activity was observed for LS 174T and PI3K beta activity for WiDr cells. This was partly correlated with an increase in p110 alpha and p110 beta protein levels both in some primary tumours and established cell lines, suggesting that PI3K overexpression is involved in enzymatic deregulation. Functional consequence of such activation was assessed by a microinjection approach. An injection of neutralizing antibody specific to p110 beta in WiDr, HCT116 and CO 115 cells inhibited de novo DNA synthesis, whereas antibodies specific to p110 gamma had no effect. Neutralizing antibodies specific to p110 alpha induced apoptosis, a response that was reverted by treating cells with the caspase inhibitor z-VAD-fmk. However anti-p110 beta and anti-p110 gamma antibodies did not affect cell survival, We concluded that PI3K alpha and PI3K beta play important roles in human colon cancer cell growth with a specific function for PI3K beta in de novo DNA synthesis and an involvement of PI3K alpha in cell survival.