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Inhibition of tumor growth by a newly-identified activator for epidermal fatty acid binding protein.

Rao E, Singh P, Zhai X, Li Y, Zhu G, Zhang Y, Hao J, Chi YI, Brown RE, Cleary MP, Li B - Oncotarget (2015)

Bottom Line: Although EI-05 is unable to bind E-FABP directly, it significantly increases E-FABP expression in macrophages during inflammation.Stimulation of macrophages with EI-05 remarkably enhances lipid droplet formation and IFNβ production, which further promotes the anti-tumor activity of macrophages.Altogether, these results suggest that EI-05 may represent a promising drug candidate for anti-tumor treatment through enhancing E-FABP activity and IFNβ responses in macrophages.

View Article: PubMed Central - PubMed

Affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.

ABSTRACT
Our previous studies have demonstrated that expression of epidermal fatty acid binding protein (E-FABP) in tumor associated macrophages (TAMs) promotes macrophage anti-tumor activity by enhancing IFNβ responses in tumor models. Thus, E-FABP represents a new protective factor in enhancing tumor immune surveillance against tumor development. Herein, we report the compound 5-(benzylamino)-2-(3-methylphenyl)-1,3-oxazole-4-carbonitrile (designated EI-05) as a novel E-FABP activator for inhibition of mammary tumor growth. EI-05 was selected from the ZINC compound library using molecular docking analysis based on the crystal structure of E-FABP. Although EI-05 is unable to bind E-FABP directly, it significantly increases E-FABP expression in macrophages during inflammation. Stimulation of macrophages with EI-05 remarkably enhances lipid droplet formation and IFNβ production, which further promotes the anti-tumor activity of macrophages. Importantly, administering EI-05 in vivo significantly inhibits mammary tumor growth in a syngeneic mouse model. Altogether, these results suggest that EI-05 may represent a promising drug candidate for anti-tumor treatment through enhancing E-FABP activity and IFNβ responses in macrophages.

No MeSH data available.


Related in: MedlinePlus

EI-05 enhances E-FABP expression in macrophagesMacrophages from a cell line (A) or bone-marrow (GM-BMMs) (B) were activated by LPS (10ng/ml) in the presence of absence of screened E-FABP partners (20 μM) for 24 h in vitro, respectively (**, p < 0.01 as compared to DMSO group). E-FABP expression was quantified by qPCR. Mice were i.p. injected with EI-05 (10 mg/kg) and vehicle control for 24 h, respectively. PBMCs were measured for E-FABP expression by western blot (C). Peritoneal macrophages were analyzed for E-FABP expression by confocal staining (D).
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Figure 2: EI-05 enhances E-FABP expression in macrophagesMacrophages from a cell line (A) or bone-marrow (GM-BMMs) (B) were activated by LPS (10ng/ml) in the presence of absence of screened E-FABP partners (20 μM) for 24 h in vitro, respectively (**, p < 0.01 as compared to DMSO group). E-FABP expression was quantified by qPCR. Mice were i.p. injected with EI-05 (10 mg/kg) and vehicle control for 24 h, respectively. PBMCs were measured for E-FABP expression by western blot (C). Peritoneal macrophages were analyzed for E-FABP expression by confocal staining (D).

Mentions: When we activated a macrophage cell line with LPS in the presence or absence of EI-05 and other potential E-FABP partners identified by computational modeling analysis, we found that EI-05, but not other small molecules, significantly enhanced E-FABP expression in macrophages (Figure 2A). We further investigated the effect of EI-05 on E-FABP expression with primary GM-CSF-induced macrophages derived from mouse bone marrow (GM-BMMs). We demonstrated that E-FABP expression in EI-05-stimulated macrophages was about 4.5 fold higher than that in control groups (Figure 2B). Consistent with these in vitro observations, when EI-05 was administered in vivo, it was able to greatly enhance E-FABP expression in macrophages of the peripheral blood as shown by western blot analysis (Figure 2C). Confocal microscopy staining further demonstrated that EI-05 treatment greatly enhanced E-FABP expression in the cytoplasm of macrophages (Figure 2D). Thus, these data suggest that EI-05 can activate macrophages through enhanced E-FABP expression in both in vitro and in vivo conditions.


Inhibition of tumor growth by a newly-identified activator for epidermal fatty acid binding protein.

Rao E, Singh P, Zhai X, Li Y, Zhu G, Zhang Y, Hao J, Chi YI, Brown RE, Cleary MP, Li B - Oncotarget (2015)

EI-05 enhances E-FABP expression in macrophagesMacrophages from a cell line (A) or bone-marrow (GM-BMMs) (B) were activated by LPS (10ng/ml) in the presence of absence of screened E-FABP partners (20 μM) for 24 h in vitro, respectively (**, p < 0.01 as compared to DMSO group). E-FABP expression was quantified by qPCR. Mice were i.p. injected with EI-05 (10 mg/kg) and vehicle control for 24 h, respectively. PBMCs were measured for E-FABP expression by western blot (C). Peritoneal macrophages were analyzed for E-FABP expression by confocal staining (D).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4480718&req=5

Figure 2: EI-05 enhances E-FABP expression in macrophagesMacrophages from a cell line (A) or bone-marrow (GM-BMMs) (B) were activated by LPS (10ng/ml) in the presence of absence of screened E-FABP partners (20 μM) for 24 h in vitro, respectively (**, p < 0.01 as compared to DMSO group). E-FABP expression was quantified by qPCR. Mice were i.p. injected with EI-05 (10 mg/kg) and vehicle control for 24 h, respectively. PBMCs were measured for E-FABP expression by western blot (C). Peritoneal macrophages were analyzed for E-FABP expression by confocal staining (D).
Mentions: When we activated a macrophage cell line with LPS in the presence or absence of EI-05 and other potential E-FABP partners identified by computational modeling analysis, we found that EI-05, but not other small molecules, significantly enhanced E-FABP expression in macrophages (Figure 2A). We further investigated the effect of EI-05 on E-FABP expression with primary GM-CSF-induced macrophages derived from mouse bone marrow (GM-BMMs). We demonstrated that E-FABP expression in EI-05-stimulated macrophages was about 4.5 fold higher than that in control groups (Figure 2B). Consistent with these in vitro observations, when EI-05 was administered in vivo, it was able to greatly enhance E-FABP expression in macrophages of the peripheral blood as shown by western blot analysis (Figure 2C). Confocal microscopy staining further demonstrated that EI-05 treatment greatly enhanced E-FABP expression in the cytoplasm of macrophages (Figure 2D). Thus, these data suggest that EI-05 can activate macrophages through enhanced E-FABP expression in both in vitro and in vivo conditions.

Bottom Line: Although EI-05 is unable to bind E-FABP directly, it significantly increases E-FABP expression in macrophages during inflammation.Stimulation of macrophages with EI-05 remarkably enhances lipid droplet formation and IFNβ production, which further promotes the anti-tumor activity of macrophages.Altogether, these results suggest that EI-05 may represent a promising drug candidate for anti-tumor treatment through enhancing E-FABP activity and IFNβ responses in macrophages.

View Article: PubMed Central - PubMed

Affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.

ABSTRACT
Our previous studies have demonstrated that expression of epidermal fatty acid binding protein (E-FABP) in tumor associated macrophages (TAMs) promotes macrophage anti-tumor activity by enhancing IFNβ responses in tumor models. Thus, E-FABP represents a new protective factor in enhancing tumor immune surveillance against tumor development. Herein, we report the compound 5-(benzylamino)-2-(3-methylphenyl)-1,3-oxazole-4-carbonitrile (designated EI-05) as a novel E-FABP activator for inhibition of mammary tumor growth. EI-05 was selected from the ZINC compound library using molecular docking analysis based on the crystal structure of E-FABP. Although EI-05 is unable to bind E-FABP directly, it significantly increases E-FABP expression in macrophages during inflammation. Stimulation of macrophages with EI-05 remarkably enhances lipid droplet formation and IFNβ production, which further promotes the anti-tumor activity of macrophages. Importantly, administering EI-05 in vivo significantly inhibits mammary tumor growth in a syngeneic mouse model. Altogether, these results suggest that EI-05 may represent a promising drug candidate for anti-tumor treatment through enhancing E-FABP activity and IFNβ responses in macrophages.

No MeSH data available.


Related in: MedlinePlus