Protein kinase A antagonist inhibits β-catenin nuclear translocation, c-Myc and COX-2 expression and tumor promotion in Apc(Min/+) mice.
Protein kinase A antagonist inhibits β-catenin nuclear translocation, c-Myc and COX-2 expression and tumor promotion in Apc(Min/+) mice.
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DOI：
10.1186/1476-4598-10-149
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发表时间：
2011-12-15
期刊：
影响因子：
37.3
通讯作者：
Taskén K
中科院分区：
文献类型：
--
作者：
Brudvik KW;Paulsen JE;Aandahl EM;Roald B;Taskén K
大肠腺瘤性息肉病（APC）蛋白是控制β-catenin蛋白酶体降解并限制其核转位的破坏复合物的一部分，被认为在结直肠癌中起守门作用。破坏复合物被Wnt-Frz和前列腺素E2（PGE 2）- PI-3激酶途径抑制。最近的报道表明，PGE 2诱导的蛋白激酶A（PKA）对β-catenin的磷酸化增加了核转位，表明PGE 2对β-catenin稳态的两种作用机制。用选择性仅靶向后一种途径的PKA拮抗剂（Rp-8-Br-cAMPS）治疗自发发生肠腺瘤的ApcMin/+小鼠，可以减少肿瘤负荷，但不能减少腺瘤数量。处理组和对照组动物肠道的免疫组织化学特征显示，在Rp-8-Br-cAMPS处理后，β-连环蛋白、β-连环蛋白核转位的表达以及β-连环蛋白靶基因c-Myc和考克斯-2的表达显著下调。在人结肠癌细胞系（HCT 116）中的平行实验显示，Rp-8-Br-cAMPS阻断PGE 2诱导的β-catenin磷酸化和c-Myc上调。提示PGE 2通过PKA促进ApcMin/+小鼠体内β-catenin核转位和肿瘤发生，提示PKA对β-catenin核转位的直接调控作用在肠癌中是有效的。
The adenomatous polyposis coli (APC) protein is part of the destruction complex controlling proteosomal degradation of β-catenin and limiting its nuclear translocation, which is thought to play a gate-keeping role in colorectal cancer. The destruction complex is inhibited by Wnt-Frz and prostaglandin E2 (PGE2) - PI-3 kinase pathways. Recent reports show that PGE2-induced phosphorylation of β-catenin by protein kinase A (PKA) increases nuclear translocation indicating two mechanisms of action of PGE2 on β-catenin homeostasis. Treatment of ApcMin/+ mice that spontaneously develop intestinal adenomas with a PKA antagonist (Rp-8-Br-cAMPS) selectively targeting only the latter pathway reduced tumor load, but not the number of adenomas. Immunohistochemical characterization of intestines from treated and control animals revealed that expression of β-catenin, β-catenin nuclear translocation and expression of the β-catenin target genes c-Myc and COX-2 were significantly down-regulated upon Rp-8-Br-cAMPS treatment. Parallel experiments in a human colon cancer cell line (HCT116) revealed that Rp-8-Br-cAMPS blocked PGE2-induced β-catenin phosphorylation and c-Myc upregulation. Based on our findings we suggest that PGE2 act through PKA to promote β-catenin nuclear translocation and tumor development in ApcMin/+ mice in vivo, indicating that the direct regulatory effect of PKA on β-catenin nuclear translocation is operative in intestinal cancer.
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影响因子：
64.5
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