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Tumor associated macrophages protect colon cancer cells from TRAIL-induced apoptosis through IL-1beta-dependent stabilization of Snail in tumor cells.

Kaler P, Galea V, Augenlicht L, Klampfer L - PLoS ONE (2010)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Albert Einstein Cancer Center, Montefiore Medical Center, New York, New York, United States of America.

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.

Principal findings: 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.

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-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.

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Crosstalk between tumor cells and macrophages which propagates the growth and survival of cancer cells.Tumor cells activate macrophages to secrete IL-1β which in a NF-κB/AKT dependent manner inactivates GSK3β and thus promotes Wnt signaling in tumor cells. Elevated levels of c-myc contribute to enhanced growth of tumor cells, while increased levels of Snail contribute to enhanced Wnt signaling, protect cells from TRAIL induced apoptosis, and are likely to contribute to the epithelial mesenchymal transition (EMT) and enhanced metastatic potential of tumor cells.
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pone-0011700-g009: Crosstalk between tumor cells and macrophages which propagates the growth and survival of cancer cells.Tumor cells activate macrophages to secrete IL-1β which in a NF-κB/AKT dependent manner inactivates GSK3β and thus promotes Wnt signaling in tumor cells. Elevated levels of c-myc contribute to enhanced growth of tumor cells, while increased levels of Snail contribute to enhanced Wnt signaling, protect cells from TRAIL induced apoptosis, and are likely to contribute to the epithelial mesenchymal transition (EMT) and enhanced metastatic potential of tumor cells.

Mentions: These data established a pivotal role of Snail in inflammation-induced resistance of tumor cells to TRAIL (Fig. 9).


Tumor associated macrophages protect colon cancer cells from TRAIL-induced apoptosis through IL-1beta-dependent stabilization of Snail in tumor cells.

Kaler P, Galea V, Augenlicht L, Klampfer L - PLoS ONE (2010)

Crosstalk between tumor cells and macrophages which propagates the growth and survival of cancer cells.Tumor cells activate macrophages to secrete IL-1β which in a NF-κB/AKT dependent manner inactivates GSK3β and thus promotes Wnt signaling in tumor cells. Elevated levels of c-myc contribute to enhanced growth of tumor cells, while increased levels of Snail contribute to enhanced Wnt signaling, protect cells from TRAIL induced apoptosis, and are likely to contribute to the epithelial mesenchymal transition (EMT) and enhanced metastatic potential of tumor cells.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2908545&req=5

pone-0011700-g009: Crosstalk between tumor cells and macrophages which propagates the growth and survival of cancer cells.Tumor cells activate macrophages to secrete IL-1β which in a NF-κB/AKT dependent manner inactivates GSK3β and thus promotes Wnt signaling in tumor cells. Elevated levels of c-myc contribute to enhanced growth of tumor cells, while increased levels of Snail contribute to enhanced Wnt signaling, protect cells from TRAIL induced apoptosis, and are likely to contribute to the epithelial mesenchymal transition (EMT) and enhanced metastatic potential of tumor cells.
Mentions: These data established a pivotal role of Snail in inflammation-induced resistance of tumor cells to TRAIL (Fig. 9).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Albert Einstein Cancer Center, Montefiore Medical Center, New York, New York, United States of America.

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.

Principal findings: 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.

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-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.

Show MeSH
Related in: MedlinePlus