PI3K is required for the physical interaction and functional inhibition of NF-κB by β-catenin in colorectal cancer cells
PI3K is required for the physical interaction and functional inhibition of NF-κB by β-catenin in colorectal cancer cells
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DOI：
10.1016/j.bbrc.2013.03.135
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发表时间：
2013-05-17
影响因子：
3.1
通讯作者：
Deng, Jiong
中科院分区：
文献类型：
--
作者：
Liu, Jingyi;Liao, Yueling;Deng, Jiong
β-连环蛋白和PI 3 K通路的激活对于结直肠癌（CRC）的肿瘤发生至关重要。这两条通路在结直肠癌的发生和发展中是独立发挥作用还是协同发挥作用仍有争议。我们以前发现β-连环蛋白通过与p65相互作用抑制NF-κ B活化，这种抑制性相互作用涉及一种未鉴定的细胞蛋白。在这项研究中，我们发现PI 3 K对NF-κ B活性的影响依赖于CRC细胞中β-连环蛋白的水平。PI 3 K促进低β-连环蛋白RKO细胞中的NF-κ B活性;而它抑制高β-连环蛋白HCT 116、DLD-1和SW 480细胞中的NF-κ B活性。我们发现PI 3 K是β-连环蛋白对NF-κ B的物理相互作用和功能抑制所必需的。在β-连环蛋白高的CRC细胞中，PI 3 K的抑制释放了NF-κ B抑制，这赋予这些细胞对THF α和Fas诱导的细胞凋亡的易感性。这与显示在CRC样本中β-连环蛋白和活化Akt的水平均与Fas（NF-κ B的下游靶标）的表达负相关的观察结果一致。在机制上，PI 3 K亚基p85与β-连环蛋白和NF-κ B形成复合物。PI 3 K的抑制破坏了复合物的形成，导致NF-κ B活化。我们的研究不仅为PI 3 K、β-catenin和NF-κ B信号通路之间的相互作用提供了新的见解，而且还表明靶向PI 3 K可能在治疗β-catenin高水平的CRC中产生治疗效果。(C)2013 Elsevier Inc. All rights reserved.
Activation of beta-catenin and PI3K pathways are crucial for the oncogenesis of colorectal cancer (CRC). It remains controversial whether these two pathways function independently or cooperatively in the development and progression of CRC. We showed previously that beta-catenin inhibited NF-kappa B activation by interacting with p65 and this inhibitory interaction involved an unidentified cellular protein. In this study, we found that the PI3K effect on NF-kappa B activity is dependent on the level of beta-catenin in CRC cells. PI3K promoted NF-kappa B activity in the beta-catenin-low RKO cells; whereas it inhibited NF-kappa B activity in the beta-catenin-high HCT116, DLD-1, and SW480 cells. We showed that PI3K is required for the physical interaction and functional inhibition of NF-kappa B by beta-catenin. Inhibition of PI3K released NF-kappa B suppression in beta-catenin-high CRC cells, which conferred these cells with susceptibility to THF alpha- and Fas-induced apoptosis. This is consistent with the observation showing that the level of beta-catenin and activated Akt are both inversely correlated with the expression of Fas, a downstream target of NF-kappa B, in CRC specimens. Mechanistically, the PI3K subunit p85 formed a complex with beta-catenin and NF-kappa B. Inhibition of PI3K disrupted the complex formation, leading to NF-kappa B activation. Our study not only provides new insight into the cross-talk among PI3K, beta-catenin and NF-kappa B signaling pathways but also indicates that targeting PI3K may yield therapeutic efficacy in treating beta-catenin-high CRC. (C) 2013 Elsevier Inc. All rights reserved.