Tumor Associated Macrophages Protect Colon Cancer Cells from TRAIL-Induced Apoptosis through IL-1β- Dependent Stabilization of Snail in Tumor Cells

Abstract

BackgroundWe recently reported that colon tumor cells stimulate macrophages to release IL-1β, which in turn inactivates GSK3β and enhances Wnt signaling in colon cancer cells, generating a self-amplifying loop that promotes the growth of tumor cells.Principal FindingsHere we describe that macrophages protect HCT116 and Hke-3 colon cancer cells from TRAIL-induced apoptosis. Inactivation of IL-1β by neutralizing IL-1β antibody, or silencing of IL-1β in macrophages inhibited their ability to counter TRAIL-induced apoptosis. Accordingly, IL-1β was sufficient to inhibit TRAIL-induced apoptosis. TRAIL-induced collapse of the mitochondrial membrane potential (Δψ) and activation of caspases were prevented by macrophages or by recombinant IL-1β. Pharmacological inhibition of IL-1β release from macrophages by vitamin D3, a potent chemopreventive agent for colorectal cancer, restored the ability of TRAIL to induce apoptosis of tumor cells cultured with macrophages. Macrophages and IL-1β failed to inhibit TRAIL-induced apoptosis in HCT116 cells expressing dnIκB, 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-1β stabilized Snail in tumor cells in an NF-κB/Wnt dependent manner and that Snail deficient tumor cells were not protected from TRAIL-induced apoptosis by macrophages or by IL-1β, demonstrating a crucial role of Snail in the resistance of tumor cells to TRAIL.SignificanceWe 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-1β, which in turn, promotes Wnt signaling and stabilizes Snail in tumor cells, conferring resistance to TRAIL. Vitamin D3 halts this amplifying loop by interfering with the release of IL-1β from macrophages. Accordingly, vitamin D3 sensitizes tumor cells to TRAIL-induced apoptosis, suggesting that the therapeutic efficacy of TRAIL could be augmented by this readily available chemopreventive agent.

Downregulation of SNAIL sensitizes hepatocellular carcinoma cells to TRAIL-induced apoptosis by regulating the NF-κB pathway

“…A previous study demonstrated the crucial role of SNAIL in the resistance of tumor cells to TRAIL (41). As a downstream target of TRAIL, many factors acted on this role of SNAIL.…”

Immune Cells in Colorectal Cancer: Prognostic Relevance and Role of MSI

“…A positive feedback loop has been identified between tumor cells and macrophages that propagates the growth and promotes the survival of colon cancer cells: tumor cells stimulate macrophages to secrete IL-1β, which in turn, promotes Wnt signaling and stabilizes Snail in tumor cells, conferring resistance to TRAIL [26]. Furthermore, IL-1β and TAMs activate NF-κB-dependent PDK1/AKT signaling in tumor cells, and thereby inactivate GSK3β, enhance Wnt signaling and promote growth of colon cancer cells, suggesting another molecular link between inflammation and tumor growth [27].…”

Doxorubicin enhances Snail/LSD1-mediated PTEN suppression in a PARP1-dependent manner

“…9 In terms of cell survival, Snail expression has been demonstrated to confer chemoresistance on breast, colon, lung, and pancreatic cancer cells. [10][11][12][13] Mechanistically, Snail can become stabilized and bind to PTEN promoter to repress its transcription during γ radiation-induced apoptosis. 14 It has also been documented that upon doxorubicin treatment, the pro-survival Akt pathway becomes activated to render breast cancer cells resistant to druginduced apoptosis.…”