The NF-kappa B/AKT-dependent Induction of Wnt Signaling in Colon Cancer Cells by Macrophages and IL-1 beta

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 interlcukin 1 beta (1L-1 beta) dependent phosphorylation of GSK3 beta, promote Wnt signaling in colon cancer cells, demonstrating that proinflammatory cytokines can enhance TCF4/beta-catenin transcriptional activity in tumor cells. Here we investigated the pathway whereby IL-1 beta inactivates GSK3 beta 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 I kappa B (dnI kappa B), demonstrating that macrophages and IL-1 activate Wnt signaling in a NF-kappa B-dependent manner. NF-kappa B activity was required for macrophages and IL-1 to activate PDK1 and AKT in tumor cells and thereby inhibit GSK3 beta activity. Consistently, dominant negative AKT (dnAKT), or pharmacological inhibition of AKT in tumor cells, prevented macrophage/IL-1 mediated phosphorylation of GSK3 beta, 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 kappa B or AKT signaling, confirming the requirement for NF kappa B and AKT activation for the protumorigenic activity of tumor associated macrophages. Thus, we showed that IL-1 and tumor associated macrophages activate NF-kappa B-dependent PDK1/AKT signaling in tumor cells, and thereby inactivate GSK3 beta, enhance Wnt signaling and promote growth of colon cancer cells, establishing a novel molecular link between inflammation and tumor growth.