Although AIMP1 was identified as a component of the macromolecular aminoacyl tRNA synthetase complex involved in the cellular translation process, it was also found to be secreted as a cytokine having complex physiological functions. Among these, AIMP1's angiostatic and immune stimulating activities suggest its potential use as a novel antitumor therapeutic protein. Here we evaluated its antitumor efficacy in a mouse xenograft model bearing human stomach cancer cells. Intravenous injection of recombinant AIMP1 for 6 days resulted in significant decreases in both tumor volume and weight. Tumor volume decreased 31.1% and 54.0% when treated with AIMP1 at a concentration of 2 mg/kg and 10 mg/kg, respectively. Tumor weight decreased 29.1% and 52.2% when treated with AIMP1 at a concentration of 2 mg/kg and 10 mg/kg, respectively. Proliferating cell nuclear antigen (PCNA) staining of tumor tissues from AIMP1-treated mice (at both 2 mg/kg and 10 mg/kg) showed a 53% reduction of cells exhibiting an active cell cycle progression. Blood levels of tumor-suppressing cytokines such as TNF-α and IL-1β increased in AIMP1-treated mice, whereas IL-12p40 and IFN-γ levels remained unaltered. Thus, this work suggests that AIMP1 may exert its antitumor activity by inducing tumor-suppressing cytokines. In a pharmacokinetic study in rats after a single intravenous injection, AMP1 exhibited a low clearance showing a one-compartmental disposition. However, due to a low volume of distribution, AIMP1 had a short half-life of 0.1 h. In a serum stability test, AIMP1 showed a half life of >60 min in human serum, 52 min in dog serum and 32 min in rat serum. Crown
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In our previous studies, AIMP1 showed significant antitumor activity against stomach cancer cells only in combination with taxol  . We suspected that tumor tissues were not exposed to an effective dose of AIMP1 via intraperitoneal injection. In this study, we delivered AIMP1 via intravenous injection instead and found that AIMP1 itself can reduce tumor growth at a much lower dose, suggesting that the method of administration is a critical factor for the antitumor efficacy of this protein. In addition, we examined the primary cause of the AIMP1 antitumor activity shown in this work. AIMP1 was reported to induce apoptosis of endothelial cells in vitro and to cause the reduction of blood vessels on the chorioallantoic membrane of fertilized eggs  . However, no significant change in vasculature development was observed in this xenograft model (data not shown), suggesting possibilities other than anti-angiogenesis as the primary cause for tumor reduction. Since AIMP1 also induces proinflammatory responses  , and inflammatory cytokines are known to modulate tumor physiology, we investigated whether blood levels of cytokines were increased by intravenous introduction of AIMP1. In our previous report, AIMP1 upregulated proinflammatory cytokine genes such as TNF-α, MCP-1, IL-1β, IL-8, RANTES, MIP-1α, MIP-1β, and MIP-2α in THP-1 human acute monocytic leukemia cell line  . Among these AIMP1-induced cytokines, TNF-α’s antitumor activity is well documented  . We found that TNF-α was significantly higher in AIMP1-treated xenograft mice than in the control. TNF-α exerts its antitumor activity both directly through killing of tumor cells and destruction of the tumor vasculature, and indirectly at the same time through manipulation of the complex tumor physiology  . Since the reduction of blood vessels in the tumor region was not prominent in our observations, we think that the increased innate immunity maybe the main cause of in vivo antitumor effect of AIMP1. Intravenous route is generally considered a more efficient way for drug delivery although there may be some exceptional cases  . A direct and rapid systemic distribution of AIMP1 could result in more efficient contact with immune cells which produce cytokines including TNF-α. Thus intravenous injection of AIMP1 might have contributed to the improved efficacy compared with the previous one in which AIMP1 was delivered via intraperitoneal injection. This notion is also supported by previous reports describing improvement of TNF-α anticancer activity by endothelial monocyte activating polypeptide (EMAP) II [17–19] , which is the 166-amino acid- C-terminal domain of AIMP1. EMAP II induced relocalization of TNF-R1 from the Golgi apparatus to the cell surface, rendering endothelial cells sensitive to TNF-α and inducing membrane expression of the TNF-R1-associated death domain (TRADD) protein  . A moderate increase in blood IL-1β levels by treatment with AIMP1 also suggests induction of antitumor activity. Although no increase in IL-12 or IFN-γ was observed in the blood of xenograft mice treated with AIMP1 in this study, these cytokines may play a role in other cancer models.
This work was supported by the Korea Research Foundation Grant funded by the Korean Government (MOEHRD, Basic Research Promotion Fund) (KRF-2008-C00024), by [FPR08-B1-250] of 21C Frontier Functional Proteomics Project from Korean Ministry of Science & Technology, and by 2008 GRRC.
All Science Journal Classification (ASJC) codes
- Cancer Research