Decreased Systemic IGF-1 in Response to Calorie Restriction Modulates Murine Tumor Cell Growth, Nuclear Factor-kappa B Activation, and Inflammation-Related Gene Expression

作者：Harvey Alison E; Lashinger Laura M; Otto Glen; Nunez Nomeli P; Hursting Stephen D^*

来源：Molecular Carcinogenesis, 2013, 52(12): 997-1006.

DOI：10.1002/mc.21940

• dietary energy balance
• mouse model
• colon cancer
• growth factors
• cytokines

Calorie restriction (CR) prevents obesity and has potent anticancer effects associated with altered hormones and cytokines. We tested the hypothesis that CR inhibits MC38 mouse colon tumor cell growth through modulation of hormone-stimulated nuclear factor (NF)-B activation and protumorigenic gene expression. Female C57BL/6 mice were randomized (n=30/group) to receive control diet or 30% CR diet. At 20 wk, 15 mice/group were killed for body composition analysis. At 21 wk, serum was obtained for hormone analysis. At 22 wk, mice were injected with MC38 cells; tumor growth was monitored for 24 d. Gene expression in excised tumors and MC38 cells was analyzed using real-time RT-PCR. In vitro MC38 NF-B activation (by p65 ELISA and immunofluorescence) were measured in response to varying IGF-1 concentrations (1-400ng/mL). Relative to controls, CR mice had decreased tumor volume, body weight, body fat, serum IGF-1, serum leptin, and serum insulin, and increased serum adiponectin (P%26lt;0.05, each). Tumors from CR mice, versus controls, had downregulated inflammation- and/or cancer-related gene expression, including interleukin (IL)-6, IL-1, tumor necrosis factor-, cyclooxygenase-2, chemokine (C-C motif) ligand-2, S100A9, and F4/80, and upregulated 15-hydroxyprostaglandin dehydrogenase expression. In MC38 cells in vitro, IGF-1 increased NF-B activation and NF-B downstream gene expression (P%26lt;0.05, each). We conclude that CR, in association with reduced systemic IGF-1, modulates MC38 tumor growth, NF-B activation, and inflammation-related gene expression. Thus, IGF-1 and/or NF-B inhibition may pharmacologically mimic the anticancer effects of CR to break the obesity-colon cancer link.

• 出版日期2013-12