Tumor Associated Macrophages Protect Colon Cancer Cells from TRAIL-Induced Apoptosis through IL-1β-Dependent Stabilization of Snail in Tumor Cells (Publication with Expression of Concern. See vol. 17, 2022)

Background: We recently reported that colon tumor cells stimulate macrophages to release IL-1 beta, which in turn inactivates GSK3 beta and enhances Wnt signaling in colon cancer cells, generating a self-amplifying loop that promotes the growth of tumor cells. Principal Findings: Here we describe that macrophages protect HCT116 and Hke-3 colon cancer cells from TRAIL-induced apoptosis. Inactivation of IL-1 beta by neutralizing IL-1 beta antibody, or silencing of IL-1 beta in macrophages inhibited their ability to counter TRAIL-induced apoptosis. Accordingly, IL-1 beta 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-1 beta. Pharmacological inhibition of IL-1 beta 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-1 beta failed to inhibit TRAIL-induced apoptosis in HCT116 cells expressing dnI kappa B, 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-1 beta stabilized Snail in tumor cells in an NF-kappa B/Wnt dependent manner and that Snail deficient tumor cells were not protected from TRAIL-induced apoptosis by macrophages or by IL-1 beta, demonstrating a crucial role of Snail in the resistance of tumor cells to TRAIL. Significance: 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-1 beta, 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-1 beta 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.