Asano Takayuki, Yao Yixin, Zhu Jijiang, Li Donghui, Abbruzzese James L, Reddy Shrikanth A G
Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Oncogene. 2004 Nov 11;23(53):8571-80. doi: 10.1038/sj.onc.1207902.
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.
信号级联的持续激活会导致严重后果，包括细胞生长控制丧失和肿瘤转化。我们在此表明，磷脂酰肌醇3激酶（PI 3激酶）及其介导因子Akt在胰腺癌中持续激活，这可能归因于其天然拮抗剂MMAC/PTEN的异常表达。实际上，我们的结果显示，在所检测的8个细胞系中的5个以及17个肿瘤标本中的12个中，MMAC/PTEN表达缺失或显著降低。甲基化特异性PCR分析表明，胰腺癌细胞中MMAC/PTEN表达不佳可能是由于启动子甲基化。我们的研究还表明，PI 3激酶靶向胰腺癌细胞中的两个重要转录因子。持续激活的核因子κB诱导基因表达的能力以及通过苏氨酸58磷酸化减少导致的c-MYC蛋白稳定均依赖于PI 3激酶活性。当用核因子κB核转位的肽拮抗剂处理胰腺癌细胞，或用MYC的显性负性突变体稳定转染时，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途径及其转录因子介导因子的激活。
