The NF-IoB/AKT-dependent Induction of Wnt Signaling in Colon Cancer Cells by Macrophages and IL-1I2

• Published in: Cancer microenvironment 2009-12, Vol.2 (1), p.69-80
• Main Authors: Kaler, Pawan, Godasi, Bramara N, Augenlicht, Leonard, Klampfer, Lidija
• Format: Article
• Language: English
• ISSN: 1875-2292; 1875-2284
• DOI: 10.1007/s12307-009-0030-y

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 1I2 (IL-1I2) dependent phosphorylation of GSK3I2, promote Wnt signaling in colon cancer cells, demonstrating that proinflammatory cytokines can enhance TCF4/I2-catenin transcriptional activity in tumor cells. Here we investigated the pathway whereby IL-1I2 inactivates GSK3I2 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 IIoB (dnIIoB), demonstrating that macrophages and IL-1 activate Wnt signaling in a NF-IoB-dependent manner. NF-IoB activity was required for macrophages and IL-1 to activate PDK1 and AKT in tumor cells and thereby inhibit GSK3I2 activity. Consistently, dominant negative AKT (dnAKT), or pharmacological inhibition of AKT in tumor cells, prevented macrophage/IL-1 mediated phosphorylation of GSK3I2, 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-IoB or AKT signaling, confirming the requirement for NF-IoB and AKT activation for the protumorigenic activity of tumor associated macrophages. Thus, we showed that IL-1 and tumor associated macrophages activate NF-IoB-dependent PDK1/AKT signaling in tumor cells, and thereby inactivate GSK3I2, enhance Wnt signaling and promote growth of colon cancer cells, establishing a novel molecular link between inflammation and tumor growth.