Abstract
Type 2 diabetes (T2D) is associated with increased risk of cancers. In this connection, we previously demonstrated the promoting effect of diabetes on HPV-associated carcinogenesis using a xenograft model in db/db diabetic mice. The underlying mechanism of this observation might be partly contributed by dysregulated immune response in diabetes. In this study, we hypothesized that the impaired anti-tumor immune response in diabetic status could be modulated by exendin-4, a glucagon-like protein receptor agonist which exhibits anti-diabetic effects. We inoculated 10-week old db/db mice with 2 × 107 CUP-1 cells (Human Papilloma Virus (HPV)-16 E7 transfected continuous cell line) subcutaneously underneath the scruff, and treated mice with high (30 nmol/kg) or low (10 nmol/kg) dose of exendin-4 for 13 days. Compared with control groups, exendin-4 suppressed subcutaneous tumor growth in a dose-dependent manner, accompanied by increased interferon (IFN)-γ secreting CD8+ cytotoxic T lymphocyte (CTL)/Foxp3+ regulatory T cell (Treg) ratio as well as Th1 proinflammatory cytokines IFN-γ and IL-2. Collectively, these findings suggested an anti-tumor effect of exendin-4 in diabetic conditions, which might be resulted from direct immunomodulation.
Highlights
Type 2 diabetes (T2D) is associated with increased risk of cancers
Our group has reported that T2D patients exhibited activated inflammatory responses of peripheral blood mononuclear cells (PBMC) which were attenuated by exendin-4 in ex vivo experiments[15]
Histological examination by haematoxylin-eosin (HE) staining confirmed presence of malignant cells in the tumor mass[16]. These results showed that the tumorigenicity of Chinese University Papillomavirus-1 (CUP-1) cells in db/db mice was further exacerbated by increasing age and severity of diabetes
Summary
Type 2 diabetes (T2D) is associated with increased risk of cancers. In this connection, we previously demonstrated the promoting effect of diabetes on HPV-associated carcinogenesis using a xenograft model in db/db diabetic mice. Exendin-4 suppressed subcutaneous tumor growth in a dose-dependent manner, accompanied by increased interferon (IFN)-γ secreting CD8+ cytotoxic T lymphocyte (CTL)/Foxp3+ regulatory T cell (Treg) ratio as well as Th1 proinflammatory cytokines IFN-γ and IL-2. These findings suggested an anti-tumor effect of exendin-4 in diabetic conditions, which might be resulted from direct immunomodulation. Receptor activation might have additional roles other than glucose-lowering effects These data indicate the potential of exendin-4 for improving anti-tumor immune response which is critical for protection against cancer growth
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