The PI 3-kinase/Akt signaling pathway is activated due to aberrant Pten expression and targets transcription factors NF-κB and c-Myc in pancreatic cancer cells
The PI 3-kinase/Akt signaling pathway is activated due to aberrant Pten expression and targets transcription factors NF-κB and c-Myc in pancreatic cancer cells
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DOI：
10.1038/sj.onc.1207902
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发表时间：
2004-11-11
期刊：
影响因子：
8
通讯作者：
Reddy, SAG
中科院分区：
文献类型：
--
作者：
Asano, T;Yao, YX;Reddy, SAG
信号级联的持续激活会导致严重的后果，包括细胞生长控制的丧失和肿瘤转化。我们在此发现，磷脂肌肽3-激酶（PI 3-激酶）及其中介体Akt在胰腺癌中组成性激活，这可能是由于其天然拮抗剂MMAC/PTEN的异常表达。事实上，我们的结果表明，MMAC/PTEN在8个细胞系中的5个以及17个肿瘤标本中的12个中表达缺失或显著降低。甲基化特异性PCR分析提示MMAC/PTEN在胰腺癌细胞中的低表达可能与启动子甲基化有关。我们的研究还表明，PI 3-激酶靶向胰腺癌细胞中两个重要的转录因子。组成性激活NF-kappaB诱导基因表达的能力以及通过降低Thr58磷酸化来稳定c-MYC蛋白的能力都依赖于PI 3-激酶活性。当胰腺癌细胞用NF-kappaB核易位肽拮抗剂处理，或稳定地用MYC的显性阴性突变体转染时，它们的增殖明显受到抑制。综上所述，这些数据表明MMAC/PTEN的异常表达有助于胰腺癌中PI 3-激酶/Akt通路及其转录因子介质的激活。
The persistent activation of signaling cascades results in dramatic consequences that include loss of cellular growth control and neoplastic transformation. We show here that phosphoinositide 3-kinase (PI 3-kinase) and its mediator Akt were constitutively activated in pancreatic cancer and that this might be due to the aberrant expression of their natural antagonist MMAC/PTEN. Indeed, our results show that MMAC/PTEN expression was either lost or significantly reduced in five of eight cell lines and in twelve of seventeen tumor specimens examined. That the poor expression of MMAC/PTEN in pancreatic cancer cells could be due to promoter methylation was indicated by methylation-specific PCR analysis. Our studies also indicated that PI 3-kinase targeted two important transcription factors in pancreatic cancer cells. The ability of constitutively activated NF-kappaB to induce gene expression and the stabilization of c-MYC protein by decreased phosphorylation of Thr58 were both dependent on PI 3-kinase activity. When pancreatic cancer cells were treated with a peptide antagonist of NF-kappaB nuclear translocation, or stably transfected with a dominant-negative mutant of MYC, their proliferation was markedly inhibited. Taken together, these data indicate that the aberrant expression of MMAC/PTEN contributes to the activation of the PI 3-kinase/Akt pathway and its transcription factor mediators in pancreatic cancer.