title: Tumor associated macrophages protect colon cancer cells from TRAIL-induced apoptosis through IL-1beta-dependent stabilization of Snail in tumor cells.
abstract: BACKGROUND
  We recently reported that colon tumor cells stimulate macrophages to release IL-1beta, which in turn inactivates GSK3beta and enhances Wnt signaling in colon cancer cells, generating a self-amplifying loop that promotes the growth of tumor cells.
  
  
  RESULTS
  Here we describe that macrophages protect HCT116 and Hke-3 colon cancer cells from TRAIL-induced apoptosis. Inactivation of IL-1beta by neutralizing IL-1beta antibody, or silencing of IL-1beta in macrophages inhibited their ability to counter TRAIL-induced apoptosis. Accordingly, IL-1beta was sufficient to inhibit TRAIL-induced apoptosis. TRAIL-induced collapse of the mitochondrial membrane potential (Delta psi) and activation of caspases were prevented by macrophages or by recombinant IL-1beta. Pharmacological inhibition of IL-1beta release from macrophages by vitamin D(3), a potent chemopreventive agent for colorectal cancer, restored the ability of TRAIL to induce apoptosis of tumor cells cultured with macrophages. Macrophages and IL-1beta failed to inhibit TRAIL-induced apoptosis in HCT116 cells expressing dnIkappaB, dnAKT or dnTCF4, confirming that they oppose TRAIL-induced cell death through induction of Wnt signaling in tumor cells. We showed that macrophages and IL-1beta stabilized Snail in tumor cells in an NF-kappaB/Wnt dependent manner and that Snail deficient tumor cells were not protected from TRAIL-induced apoptosis by macrophages or by IL-1beta, demonstrating a crucial role of Snail in the resistance of tumor cells to TRAIL.
  
  
  CONCLUSIONS
  We have identified a positive feedback loop between tumor cells and macrophages that propagates the growth and promotes the survival of colon cancer cells: tumor cells stimulate macrophages to secrete IL-1beta, which in turn, promotes Wnt signaling and stabilizes Snail in tumor cells, conferring resistance to TRAIL. Vitamin D(3) halts this amplifying loop by interfering with the release of IL-1beta from macrophages. Accordingly, vitamin D(3) sensitizes tumor cells to TRAIL-induced apoptosis, suggesting that the therapeutic efficacy of TRAIL could be augmented by this readily available chemopreventive agent.
authors.affiliation: Department of Oncology, Albert Einstein Cancer Center, Montefiore Medical Center, New York, New York, United States of America.
authors.forename: Pawan
authors.initials: P
authors.lastname: Kaler
authors.forename: Vincent
authors.initials: V
authors.lastname: Galea
authors.forename: Leonard
authors.initials: L
authors.lastname: Augenlicht
authors.forename: Lidija
authors.initials: L
authors.lastname: Klampfer
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002762:Cholecalciferol / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D000071250:Snail Family Transcription Factors; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D000071250:Snail Family Transcription Factors; D053221:TNF-Related Apoptosis-Inducing Ligand; D014157:Transcription Factors; D051153:Wnt Proteins; D002762:Cholecalciferol