Abstract 4100: The anticancer effects of calorie restriction on Panc 02 pancreatic tumors are associated with decreased activation of NF-kB
Authors: Alison E. Harvey, Laura M. Lashinger, Lauren M. Malone, Susan N. Perkins, Stephen D. Hursting
Journal: Cancer Research (2010)

Abstract Calorie restriction (CR), an anti-obesity dietary regimen with potent anti-cancer effects, reduces serum levels of metabolic hormones and protumorigenic cytokines. Independent of diet, metabolism-related hormones such as insulin-like growth factor (IGF)-1 and leptin have been shown to activate the inflammatory signal transduction pathway regulated by nuclear factor (NF)-κB. NF-κB is a transcription factor that is upregulated in over 70% of human pancreatic cancer cell lines and primary tumors. In this study we tested the hypothesis that CR inhibits pancreatic tumor cell growth in part through modulation of hormone-stimulated NF-κB activation and downstream protumorigenic gene expression. Six-week-old male C57BL/6 mice (n=12 per diet) were singly housed and randomized to either a control diet consumed ad libitum (which results in an overweight phenotype) or a 30% CR diet regimen for 22 weeks, at which time mice were fasted and blood was collected for serum metabolic hormone analysis. At week 23, mice were injected subcutaneously (left flank) with 1 × 10^6 syngeneic mouse pancreatic cancer cells (Panc 02) and maintained on their diet regimens while tumor growth was monitored for an additional 4 weeks. Excised tumors underwent real-time RT-PCR analysis of protumorigenic cytokine gene expression. CR mice had lower body weight (19.0 g +/− 0.4 vs. 33.0 +/− 0.6 (mean +/− SEM) p&amp;lt;0.05) and reduced levels of circulating leptin (1.13 ng/mL +/− 0.2 vs. 5.04 +/−1.2, p&amp;lt;0.05) and IGF-1 (126.4 ng/mL +/− 8.4 vs 199.1 +/− 10.6, p&amp;lt;0.05) after 22 weeks on study compared to control mice. There was no difference in circulating insulin (0.31 ng/mL + 0.01 vs. 0.34 +/− 0.04) levels. Furthermore, CR mice had smaller tumors (220.8 mm^3 +/− 29.7 vs. 550.3 +/− 55.5, p&amp;lt;0.05) relative to controls. Tumors from CR mice, relative to controls, demonstrated an 80% decrease in expression of the protumorigenic genes IL-6, IL-1 receptor, and cyclooxygenase (COX)-2 and up to a 3-fold increase in the antitumorigenic genes IL-10, suppressor of cytokine signaling (SOCS)-1, and 15-hydroxyprostaglandin dehydrogenase (Hpgd). In vitro analysis of Panc 02 cells was also performed to assess proliferation and NF-κB transcriptional activation in response to IGF-1 and leptin. IGF-1 (10 ng/mL) increased Panc 02 cell proliferation 2.5 fold compared with serum-free control (p&amp;lt;0.05) whereas leptin (up to 200 ng/mL) had no effect on cell proliferation. Furthermore, IGF-1 (400 ng/mL) increased NF-κB pathway activation 2 fold relative to serum-free control (p&amp;lt;0.05), whereas leptin (100 ng/mL) increased NF-κB pathway activation 40% relative to serum-free control (p=0.07). These findings suggest that the inhibitory effects of CR on Panc 02 pancreatic tumor growth are, in part, associated with reduced activation of hormone-stimulated NF-κB activation, which may lead to new targets for the prevention of pancreatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4100.