Decreased systemic IGF-1 in response to calorie restriction modulates murine tumor cell growth, nuclear factor-κB activation, and inflammation-related gene expression.
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)-κB 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-κB activation (by p65 ELISA and immunofluorescence) were measured in response to varying IGF-1 concentrations (1-400 ng/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 < 0.05, each). Tumors from CR mice, versus controls, had downregulated inflammation- and/or cancer-related gene expression, including interleukin (IL)-6, IL-1β, tumor necrosis factor-α, 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-κB activation and NF-κB downstream gene expression (P < 0.05, each). We conclude that CR, in association with reduced systemic IGF-1, modulates MC38 tumor growth, NF-κB activation, and inflammation-related gene expression. Thus, IGF-1 and/or NF-κB inhibition may pharmacologically mimic the anticancer effects of CR to break the obesity-colon cancer link.
Department of Nutritional Sciences, University of Texas at Austin, Austin, Texas.
Alison E
AE
Harvey
Laura M
LM
Lashinger
Glen
G
Otto
Nomeli P
NP
Nunez
Stephen D
SD
Hursting
D000273:Adipose Tissue; D000818:Animals; D001835:Body Weight; D031204:Caloric Restriction; D003110:Colonic Neoplasms / Q000178:diet therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005786:Gene Expression Regulation; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000235:genetics*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase