The NF-κB/AKT-dependent Induction of Wnt Signaling in Colon Cancer Cells by Macrophages and IL-1β.
The NF-κB/AKT-dependent Induction of Wnt Signaling in Colon Cancer Cells by Macrophages and IL-1β.
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DOI：
10.1007/s12307-009-0030-y
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发表时间：
2009-12
影响因子：
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通讯作者：
Klampfer, Lidija
中科院分区：
文献类型：
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作者：
Kaler, Pawan;Godasi, Bramara N;Augenlicht, Leonard;Klampfer, Lidija
结肠癌从微腺瘤到肉眼可见肿瘤的进展与经典 Wnt 信号传导的增强有关。我们最近报道，肿瘤相关巨噬细胞通过白介素 1β (IL-1β) 依赖性 GSK3β 磷酸化，促进结肠癌细胞中的 Wnt 信号传导，证明促炎细胞因子可以增强肿瘤细胞中的 TCF4/β-catenin 转录活性。在这里，我们研究了结肠癌细胞中 IL-1β 灭活 GSK3β 并促进 Wnt 信号传导的途径。我们发现，正常人单核细胞、THP1 巨噬细胞和 IL-1 未能在表达显性失活 IκB (dnIκB) 的肿瘤细胞中诱导 Wnt 信号传导，表明巨噬细胞和 IL-1 以 NF-κB 依赖性方式激活 Wnt 信号传导。巨噬细胞和 IL-1 需要 NF-κB 活性来激活肿瘤细胞中的 PDK1 和 AKT，从而抑制 GSK3β 活性。一致地，显性失活 AKT (dnAKT) 或肿瘤细胞中 AKT 的药理学抑制可阻止巨噬细胞/IL-1 介导的 GSK3β 磷酸化、Wnt 信号传导的激活以及 c-jun 和 c-myc 的诱导，证实巨噬细胞和 IL-1 以 AKT 依赖性方式促进 Wnt 信号传导。最后，我们发现 IL-1 和巨噬细胞无法促进 NF-κB 或 AKT 信号传导受损的结肠癌细胞的生长，证实了肿瘤相关巨噬细胞的促肿瘤活性需要 NF-κB 和 AKT 激活。因此，我们发现IL-1和肿瘤相关巨噬细胞激活肿瘤细胞中NF-κB依赖性PDK1/AKT信号传导，从而使GSK3β失活，增强Wnt信号传导并促进结肠癌细胞的生长，在炎症和肿瘤生长之间建立新的分子联系。
Progression of colon cancer from microadenoma to macroscopic tumors is coupled to augmentation of canonical Wnt signaling. We recently reported that tumor associated macrophages, through interleukin 1β (IL-1β) dependent phosphorylation of GSK3β, promote Wnt signaling in colon cancer cells, demonstrating that proinflammatory cytokines can enhance TCF4/β-catenin transcriptional activity in tumor cells. Here we investigated the pathway whereby IL-1β inactivates GSK3β and promotes Wnt signaling in colon cancer cells. We showed that normal human monocytes, THP1 macrophages and IL-1 failed to induce Wnt signaling in tumor cells expressing dominant negative IκB (dnIκB), demonstrating that macrophages and IL-1 activate Wnt signaling in a NF-κB-dependent manner. NF-κB activity was required for macrophages and IL-1 to activate PDK1 and AKT in tumor cells and thereby inhibit GSK3β activity. Consistently, dominant negative AKT (dnAKT), or pharmacological inhibition of AKT in tumor cells, prevented macrophage/IL-1 mediated phosphorylation of GSK3β, activation of Wnt signaling, and induction of c-jun and c-myc, confirming that macrophages and IL-1 promote Wnt signaling in an AKT dependent manner. Finally, we showed IL-1 and macrophages failed to promote growth of colon cancer cells with impaired NF-κB or AKT signaling, confirming the requirement for NF-κB and AKT activation for the protumorigenic activity of tumor associated macrophages. Thus, we showed that IL-1 and tumor associated macrophages activate NF-κB-dependent PDK1/AKT signaling in tumor cells, and thereby inactivate GSK3β, enhance Wnt signaling and promote growth of colon cancer cells, establishing a novel molecular link between inflammation and tumor growth.