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首页> 外文期刊>Cancer biology & therapy >Constitutive non-canonical NFkappaB signaling in pancreatic cancer cells.
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Constitutive non-canonical NFkappaB signaling in pancreatic cancer cells.

机译：胰腺癌细胞的本构性非经典NFkappaB信号传导。

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Constitutive classical NFkappaB activation has been implicated in the development of pancreatic cancer, and inhibition of classical NFkappaB signaling sensitizes pancreatic cancer cells to apoptosis. However, the role of the more recently described non-canonical NFkappaB pathway has not been specifically addressed in pancreatic cancer. The non-canonical pathway requires stabilization of NIK and IKKalpha-dependent phosphorylation and processing of NFkappaB2/p100 to p52. This leads to the activation of p52-RelB heterodimers that regulate genes encoding lymphoid-specific chemokines and cytokines. We performed qRT-PCR to detect gene expression in a panel of pancreatic ductal adenocarcinoma cell lines (BxPC-3, PCA-2, PANC-1, Capan-1, Hs-766T, AsPC-1, MiaPACA-2) and found only modest elevation of classical NFkappaB-dependent genes. In contrast, each of the tumor cell lines displayed dramatically elevated levels of subsets of the non-canonical NFkappaB target genes CCL19, CCL21, CXCL12, CXCL13 and BAFF. Consistent with activation of the non-canonical pathway, p52 and RelB co-localized in adenocarcinoma cells in sections of pancreatic tumor tissue, and each of the tumor cell lines displayed elevated p52 levels. Furthermore, p52 and RelB co-immunoprecipitated from pancreatic cancer cells and immunoblotting revealed that NIK was stabilized and p100 was constitutively phosphorylated in a subset of the cell lines. Finally, stable overexpression of dominant negative IKKalpha significantly inhibited non-canonical target gene expression in BxPC-3 cells. These findings therefore demonstrate that the non-canonical NFkappaB pathway is constitutively active and functional in pancreatic cancer cells.
机译：组成性经典NFkappaB激活已牵涉到胰腺癌的发展，并且经典NFkappaB信号的抑制使胰腺癌细胞对凋亡敏感。然而，在胰腺癌中尚未具体解决较新描述的非规范性NFkappaB途径的作用。非规范途径需要稳定NIK和IKKalpha依赖性磷酸化，以及将NFkappaB2 / p100加工成p52。这导致p52-RelB异二聚体的激活，该异二聚体调节编码淋巴样特异性趋化因子和细胞因子的基因。我们进行了qRT-PCR检测一组胰腺导管腺癌细胞系（BxPC-3，PCA-2，PANC-1，Capan-1，Hs-766T，AsPC-1，MiaPACA-2）中的基因表达，仅发现适度提高了经典的NFkappB依赖性基因。相反，每种肿瘤细胞系都显示出非经典的NFkappaB靶基因CCL19，CCL21，CXCL12，CXCL13和BAFF的子集水平显着升高。与非经典途径的激活一致，p52和RelB共定位于胰腺肿瘤组织切片的腺癌细胞中，并且每种肿瘤细胞系均显示升高的p52水平。此外，从胰腺癌细胞中共免疫沉淀了p52和RelB，并进行了免疫印迹分析，结果表明NIK得以稳定，并且p100在部分细胞系中被组成性磷酸化。最后，显性负IKKalpha的稳定过表达显着抑制了BxPC-3细胞中非规范靶基因的表达。因此，这些发现表明，非典型的NFkappaB途径在胰腺癌细胞中具有组成性活性和功能。

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