The NF-κB/AKT-dependent induction of Wnt signaling in colon cancer cells by macrophages and IL-1β

Pawan Kaler, Bramara N. Godasi, Leonard Augenlicht, Lidija Klampfer

Research output: Contribution to journalArticle

72 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)69-80
Number of pages12
JournalCancer Microenvironment
Volume2
Issue number1
DOIs
StatePublished - Jan 1 2009

Keywords

  • Colon cancer
  • Interleukin 1
  • Macrophages
  • NF κB signaling
  • Wnt signaling

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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