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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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IL-1β is sufficient and required to protect cells from TRAIL-induced apoptosis.A and B: HCT116 cells were cultured with THP1 macrophages with silenced IL-1β or STAT1 expression and were treated with TRAIL as indicated. IL-1β was neutralized by anti-IL-1β specific antibody. Pictures were taken (A) and the amount of apoptosis (B) was determined after 7 hours. Data shown in B represent the average of three independent experiments. C and D: Studies by Gyorffy et al ([29], C) and by Khambata-Ford et al ([30], D) were surveyed through Oncomine and indicate that cell lines (C) and primary colon cancers (D) with higher levels of IL-1βdisplay resistance to therapeutic agents, such as vinblastine, doxorubicin and cetuximab (CTX).
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pone-0011700-g003: IL-1β is sufficient and required to protect cells from TRAIL-induced apoptosis.A and B: HCT116 cells were cultured with THP1 macrophages with silenced IL-1β or STAT1 expression and were treated with TRAIL as indicated. IL-1β was neutralized by anti-IL-1β specific antibody. Pictures were taken (A) and the amount of apoptosis (B) was determined after 7 hours. Data shown in B represent the average of three independent experiments. C and D: Studies by Gyorffy et al ([29], C) and by Khambata-Ford et al ([30], D) were surveyed through Oncomine and indicate that cell lines (C) and primary colon cancers (D) with higher levels of IL-1βdisplay resistance to therapeutic agents, such as vinblastine, doxorubicin and cetuximab (CTX).

Mentions: We showed that IL-1β is sufficient to inhibit TRAIL-induced apoptosis (Fig. 2). To establish whether IL-1β is required for macrophage mediated protection of tumor cells from TRAIL-induced apoptosis, we first silenced IL-1β in THP1 macrophages. These experiments revealed that IL-1β deficient macrophages fail to protect tumor cells from TRAIL-induced apoptosis (Fig. 3A and 3B). Consistent with these data, neutralization of IL-1β by IL-1β specific antibody, or silencing of STAT1, a transcription factor that we showed is required for the release of IL-1β from macrophages [7] also inhibited the anti-apoptotic activity of macrophages (Fig. 3A and 3B). As expected, neutralizing IL-1β antibody inhibited the prosurvival activity of IL-1β, demonstrating the specificity of antibody. Together, these data established that tumor associated macrophages protect tumor cells from TRAIL-induced apoptosis in an IL-1β dependent manner.


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)

IL-1β is sufficient and required to protect cells from TRAIL-induced apoptosis.A and B: HCT116 cells were cultured with THP1 macrophages with silenced IL-1β or STAT1 expression and were treated with TRAIL as indicated. IL-1β was neutralized by anti-IL-1β specific antibody. Pictures were taken (A) and the amount of apoptosis (B) was determined after 7 hours. Data shown in B represent the average of three independent experiments. C and D: Studies by Gyorffy et al ([29], C) and by Khambata-Ford et al ([30], D) were surveyed through Oncomine and indicate that cell lines (C) and primary colon cancers (D) with higher levels of IL-1βdisplay resistance to therapeutic agents, such as vinblastine, doxorubicin and cetuximab (CTX).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0011700-g003: IL-1β is sufficient and required to protect cells from TRAIL-induced apoptosis.A and B: HCT116 cells were cultured with THP1 macrophages with silenced IL-1β or STAT1 expression and were treated with TRAIL as indicated. IL-1β was neutralized by anti-IL-1β specific antibody. Pictures were taken (A) and the amount of apoptosis (B) was determined after 7 hours. Data shown in B represent the average of three independent experiments. C and D: Studies by Gyorffy et al ([29], C) and by Khambata-Ford et al ([30], D) were surveyed through Oncomine and indicate that cell lines (C) and primary colon cancers (D) with higher levels of IL-1βdisplay resistance to therapeutic agents, such as vinblastine, doxorubicin and cetuximab (CTX).
Mentions: We showed that IL-1β is sufficient to inhibit TRAIL-induced apoptosis (Fig. 2). To establish whether IL-1β is required for macrophage mediated protection of tumor cells from TRAIL-induced apoptosis, we first silenced IL-1β in THP1 macrophages. These experiments revealed that IL-1β deficient macrophages fail to protect tumor cells from TRAIL-induced apoptosis (Fig. 3A and 3B). Consistent with these data, neutralization of IL-1β by IL-1β specific antibody, or silencing of STAT1, a transcription factor that we showed is required for the release of IL-1β from macrophages [7] also inhibited the anti-apoptotic activity of macrophages (Fig. 3A and 3B). As expected, neutralizing IL-1β antibody inhibited the prosurvival activity of IL-1β, demonstrating the specificity of antibody. Together, these data established that tumor associated macrophages protect tumor cells from TRAIL-induced apoptosis in an IL-1β dependent manner.

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