Positive correlation between overexpression of phospho-BAD with phosphorylated Akt at serine 473 but not threonine 308 in colorectal carcinoma
Positive correlation between overexpression of phospho-BAD with phosphorylated Akt at serine 473 but not threonine 308 in colorectal carcinoma
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DOI：
10.1016/j.canlet.2004.01.017
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发表时间：
2004-07-16
期刊：
影响因子：
9.7
通讯作者：
Seow, HF
中科院分区：
文献类型：
--
作者：
Khor, TO;Gul, YA;Seow, HF
通过抑制细胞凋亡来促进细胞增殖和促进细胞存活被认为是癌症发生和发展的关键。磷脂酰肌醇-3激酶（PI 3 K）/Akt是重要的存活信号通路，其已被证明在促凋亡和存活（抗凋亡）信号之间的平衡的调节中至关重要。本研究采用免疫组织化学方法检测47例结直肠癌组织中Akt磷酸化位点（308位和473位）、BCL-2细胞死亡拮抗剂（BAD）位点（136位）和糖原合成酶激酶-3 β（GSK-3 β）位点（9位）的表达，以探讨结直肠癌中信号转导通路的改变。我们的研究结果表明，与明显正常的邻近组织相比，这些生物分子在CRC组织中的表达显著增加。肿瘤组织中p-Akt 1/2/3（Thr（308））的表达率为16/47（34%），p-Akt 1（Ser（473））的表达率为21/47（44.7%），磷酸化BAD（p-BAD）Ser（136）的表达率为27/47（57.4%），磷酸化GSK-3 β（p-GSK-3 β）的表达率为21/47（44.7%）。对总p-Akt 1（Ser（473））、p-Akt 1/2/3（Thr（308））、p-GSK-3 β（Ser（9））和p-BAD（Ser（136））评分的分析发现，相互之间存在统计学显著相关性。总p-Akt（Ser（473））评分与总p-GSK-3 β（Ser（9））评分以及总p-BAD（Ser（136））评分之间存在统计学显著的正线性关系。另一方面，总p-Akt 1/2/3（Thr（308））评分仅与p-GSK-3 β（Ser（9））具有统计学显著的正线性关系。Akt靶点p-GSK-3 β（Ser（9））和p-BAD（Ser（136））彼此呈正相关。除年龄外，临床病理数据与总p-Akt 1（Ser（473））、p-Akt 1/2/3（Thr（308））、p-GSK-3 β（Ser（9））和p-BAD（Ser（136））评分之间无显著相关性。发现60岁以上患者的p-GSK-3 β总分较高。这是首次报道p-Akt 1/2/3（Thr（308））和p-BAD（Ser（136））在原发性结直肠肿瘤组织中的表达。我们的数据进一步支持PI 3 K/Akt信号通路在CRC发病机制中的作用，并有助于识别癌症治疗的信号转导通路中的靶分子。(C)2004爱思唯尔爱尔兰有限公司保留所有权利。
The enhancement of cell proliferation and promotion of cell survival via the inhibition of apoptosis is thought to be the key to the initiation and progression of cancers. The phosphatidylinositol-3 kinase (PI3K)/Akt is an important survival signal pathway that has been shown to be crucial in the regulation of balance between pro-apoptotic and survival (anti-apoptotic) signal. In this study, the expression of phosphorylated Akt at Thr(308) and Ser(473), BCL-2-antagonist of cell death (BAD) at Ser(136) and glycogen synthase kinase-3beta (GSK-3beta) at Ser(9) in 47 paraffin-embedded human colorectal carcinoma (CRC) tissues were determined by immunohistochemical staining in order to dissect the alterations in the signal transduction pathways in CRC. Our results showed that there was a significant increase in the expression of these biomolecules in CRC tissues compared to the apparently normal adjacent tissues. The frequency of increased expression in tumor colonic mucosa were as follows: p-Akt1/2/3 (Thr(308)) = 16/47 (34%); p-Akt1 (Ser(473)) = 21/47 (44.7%); phospho-BAD (p-BAD) Ser(136) = 27/47 (57.4%) and phospho-GSK-3beta (p-GSK-3beta) = 21/47 (44.7%). Analysis of the total p-Akt1 (Ser(473)), p-Akt1/2/3 (Thr(308)), p-GSK-3beta (Ser(9)) and p-BAD (Ser(136)) score found that there was a statistically significant relationship with each other. A statistically significant positive linear relationship was found between total p-Akt (Ser(473)) score and total p-GSK-3beta (Ser(9)) score as well as with total p-BAD (Ser(136)) score. On the other hand, total p-Akt1/2/3 (Thr(308)) scores had a statistically significant positive linear relationship with p-GSK-3beta (Ser(9)) only. The Akt targets, p-GSK-3beta (Ser(9)) and p-BAD (Ser(136)) were positively correlated to each other. There was no significant correlation between clinico-pathological data with total p-Akt1 (Ser(473)), p-Akt1/2/3 (Thr(308)), p-GSK-3beta (Ser(9)) and p-BAD (Ser(136)) score except for age. The total scores of p-GSK-3beta were found to be higher in patients in the age group of greater than 60. This is the first report of p-Akt1/2/3 (Thr(308)) and p-BAD (Ser(136)) expression in primary colorectal tumor tissue. Our data further supports the role of PI3K/Akt signaling pathways in the pathogenesis of CRC and contributes to the identification of target molecules in the signal transduction pathway for cancer therapy. (C) 2004 Elsevier Ireland Ltd. All rights reserved.