Aberrant IKKα and IKKβ cooperatively activate NF-κB and induce EGFR/AP1 signaling to promote survival and migration of head and neck cancer.
Aberrant IKKα and IKKβ cooperatively activate NF-κB and induce EGFR/AP1 signaling to promote survival and migration of head and neck cancer.
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抑制剂-κB激酶-核因子-κB（IKK-NF-κB）和表皮生长因子受体激活蛋白-1（EGFR-AP-1）通路通常被共激活并促进恶性行为，但这种关系的潜在基础尚不清楚。在头颈部鳞状细胞癌（HNSCC）中观察到对IKKβ或EGFR抑制剂的耐药性。在这里，我们发现IKKα和IKK β都有助于经典和替代NF-κB/REL家族转录因子的核激活，以及增强EGFR-AP 1通路共激活的信号成分的过表达。我们观察到IKKα和IKKβ在HNSCC组织和细胞系中表现出蛋白表达、核定位和磷酸化增加。个别地，IKK活性在不同的细胞系中不同，但是两种IKK的过表达诱导最强的NF-κB活化。相反，siRNA敲除两种IKK均显著降低经典RELA和IκBα以及替代性p52和RELB亚基的核定位和磷酸化。敲除两种IKK可更有效地抑制NF-κB活化，广泛调节基因表达，并抑制细胞增殖和迁移。总体表达谱显示NF-κB、细胞因子、炎症反应和生长因子信号传导是IKK调控的主要途径和网络。重要的是，IKKα和IKKβ共同促进TGFα、EGFR和AP 1转录因子cJun、JunB和Fra 1的表达和活性。敲除AP 1亚基单独降低了8/15（53%）的IKK靶向基因采样，并类似地抑制细胞增殖和迁移。NF-κB和AP 1结合位点的突变消除或降低IKK诱导的IL-8启动子活性。具有双重IKK抑制活性的化合物，如wedelactone和阻断IKKα/β和EGFR途径的geldanomycins，在抑制NF-κB活化和增殖以及诱导细胞死亡方面比IKKβ特异性抑制剂更有效。结论IKKα和IKKβ协同激活NF-κB和EGFR/AP 1信号通路网络，参与HNSCC的恶性表型和内在或获得性耐药。
The Inhibitor-κB Kinase-Nuclear Factor-κB (IKK-NF-κB) and Epidermal Growth Factor Receptor-Activator Protein-1 (EGFR-AP-1) pathways are often co-activated and promote malignant behavior, but the underlying basis for this relationship is unclear. Resistance to inhibitors of IKKβ or EGFR is observed in head and neck squamous cell carcinomas (HNSCC). Here, we reveal that both IKKα and β contribute to nuclear activation of canonical and alternate NF-κB/REL family transcription factors, and overexpression of signal components enhancing co-activation of the EGFR-AP1 pathway. We observed that IKKα and IKKβ exhibit increased protein expression, nuclear localization and phosphorylation in HNSCC tissues and cell lines. Individually, IKK activity varied amongst different cell lines, but overexpression of both IKKs induced the strongest NF-κB activation. Conversely, siRNA knockdown of both IKKs significantly decreased nuclear localization and phosphorylation of canonical RELA and IκBα, and alternative p52 and RELB subunits. Knockdown of both IKKs more effectively inhibited NF-κB activation, broadly modulated gene expression, and suppressed cell proliferation and migration. Global expression profiling revealed that NF-κB, cytokine, inflammatory response, and growth factor signaling are among the top pathways and networks regulated by IKKs. Importantly, IKKα and IKKβ together promoted the expression and activity of TGFα, EGFR, and AP1 transcription factors cJun, JunB, and Fra1. Knockdown of AP1 subunits individually decreased 8/15 (53%) of IKK-targeted genes sampled, and similarly inhibited cell proliferation and migration. Mutations of NF-κB and AP1 binding sites abolished or decreased IKK-induced IL-8 promoter activity. Compounds such as wedelactone with dual IKK inhibitory activity, and geldanomycins that block IKKα/β and EGFR pathways were more active than IKKβ-specific inhibitors in suppressing NF-κB activation and proliferation, and inducing cell death. We conclude that IKKα and IKKβ cooperatively activate NF-κB and EGFR/AP1 networks of signaling pathways, and contribute to the malignant phenotype and the intrinsic or acquired therapeutic resistance of HNSCC.
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