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In vitro and in vivo anticancer activity of a synthetic glycolipid as Toll-like receptor 4 (TLR4) activator.

ABSTRACT: Activation of Toll-like receptor 4 (TLR4) triggers the innate immune response and leads to the induction of adaptive immunity. TLR4 agonists are known to function as immunostimulants and exhibit promising therapeutic potential for cancer immunotherapy. We have previously developed a synthetic serine-based glycolipid (designated as CCL-34) that can activate TLR4-dependent signaling pathways. In this study, the anticancer immunity of CCL-34 was further demonstrated. CCL-34-activated macrophages induced cancer cell death via the apoptotic pathway, and this cytotoxicity was significantly inhibited by NG-monomethyl-L-arginine (an inducible NOS inhibitor). Notably, conditioned medium collected from CCL-34-treated splenocytes also induced cytotoxicity toward cancer cells. Furthermore, CCL-34 treatment suppressed tumor growth and increased the survival rate in TLR4-functional C3H/HeN mice but not in TLR4-defective C3H/HeJ mice. Increased apoptosis, the induction of cytokines (IFN-? and IL-12) and chemokines (CXCL9 and CXCL10), and the elevation of leukocyte markers (CD11b, CD11c, CD4, and CD8) were detected at tumor sites in C3H/HeN mice but not in C3H/HeJ mice. Structure-and-activity relationship analysis of CCL-34 and its structural analogs revealed that a sugar moiety is essential for its activity. However, the substitution of the galactose in CCL-34 with glucose or fucose did not reduce its activity. Altogether, this study reveals the anticancer activity of a new synthetic TLR4 agonist and broadens the molecular basis of TLR4-activating glycolipids.

SUBMITTER: Lin YS

PROVIDER: S-EPMC3243550 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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In vitro and in vivo anticancer activity of a synthetic glycolipid as Toll-like receptor 4 (TLR4) activator.

Lin Yong-Shiang YS Huang Li-De LD Lin Chao-Hsiung CH Huang Po-Hsiung PH Chen Yu-Jen YJ Wong Fen-Hwa FH Lin Chun-Cheng CC Fu Shu-Ling SL

The Journal of biological chemistry 20110923 51

Activation of Toll-like receptor 4 (TLR4) triggers the innate immune response and leads to the induction of adaptive immunity. TLR4 agonists are known to function as immunostimulants and exhibit promising therapeutic potential for cancer immunotherapy. We have previously developed a synthetic serine-based glycolipid (designated as CCL-34) that can activate TLR4-dependent signaling pathways. In this study, the anticancer immunity of CCL-34 was further demonstrated. CCL-34-activated macrophages in ...[more]

PMID: 21949133

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Project description:Genetically engineered mice are a valuable resource for studies of the behavioral effects of ethanol. However, for some behavioral tests of ethanol action, the rat is a superior model organism. Production of genetically engineered rats has been severely hampered due to technical limitations. Here we utilized a promising new technique for efficient site-specific gene modification to create a novel gene knockout rat line. This approach is based on transcriptional activator-like effector nucleases (TALENs). TALENs function in pairs and bind DNA in a sequence-specific manner. Upon binding to the target sequence, a functional nuclease is reconstituted that creates double-stranded breaks in the DNA that are efficiently repaired by non-homologous end joining. This error-prone process often results in deletions of varying lengths at the targeted locus. The toll-like receptor 4 (Tlr4) gene was selected for TALEN-mediated gene inactivation. Tlr4 has been implicated in ethanol-induced neuroinflammation and neurodegeneration, as well as multiple ethanol-induced behavioral effects. To generate Tlr4 knockout rats, a pair of TALEN constructs was created that specifically target Exon 1 immediately downstream of the start of translation. TALEN mRNAs were microinjected into the cytoplasm of one-cell Wistar rat embryos. Of 13 live-born pups that resulted, one harbored a mutation in Exon 1 of Tlr4. The mutated allele consisted of a 13 base-pair deletion that was predicted to create a frameshift mutation after amino acid 25. This founder rat successfully transmitted the mutation to F1 offspring. Heterozygous F1 offspring were interbred to produce homozygous F2 animals. Homozygous mutants expressed the 13-bp deletion in Tlr4 mRNA. In contrast to control rats that produced a robust increase in plasma tumor necrosis factor alpha in response to a lipopolysaccharide challenge, homozygous rats had a markedly attenuated response. Thus, the mutant Tlr4 allele generated by TALEN-mediated gene inactivation represents a null allele. This knockout rat line will be valuable for studies of ethanol action as well as more general inflammatory conditions including septic shock. In conclusion, TALEN-mediated gene targeting in rat zygotes represents an inexpensive, efficient, and rapid method for creating genetically engineered rats.

Dataset Information

In vitro and in vivo anticancer activity of a synthetic glycolipid as Toll-like receptor 4 (TLR4) activator.

Publications

In vitro and in vivo anticancer activity of a synthetic glycolipid as Toll-like receptor 4 (TLR4) activator.

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