Abstract
Calorie restriction (CR) prevents obesity and has potent anticancer effects that may be mediated through its ability to reduce serum growth and inflammatory factors, particularly insulin-like growth factor (IGF)-1 and protumorigenic cytokines. IGF-1 is a nutrient-responsive growth factor that activates the inflammatory regulator nuclear factor (NF)-κB, which is linked to many types of cancers, including pancreatic cancer. We hypothesized that CR would inhibit pancreatic tumor growth through modulation of IGF-1-stimulated NF-κB activation and protumorigenic gene expression. To test this, 30 male C57BL/6 mice were randomized to either a control diet consumed ad libitum or a 30% CR diet administered in daily aliquots for 21 weeks, then were subcutaneously injected with syngeneic mouse pancreatic cancer cells (Panc02) and tumor growth was monitored for 5 weeks. Relative to controls, CR mice weighed less and had decreased serum IGF-1 levels and smaller tumors. Also, CR tumors demonstrated a 70% decrease in the expression of genes encoding the pro-inflammatory factors S100a9 and F4/80, and a 56% decrease in the macrophage chemoattractant, Ccl2. Similar CR effects on tumor growth and NF-κB-related gene expression were observed in a separate study of transplanted MiaPaCa-2 human pancreatic tumor cell growth in nude mice. In vitro analyses in Panc02 cells showed that IGF-1 treatment promoted NF-κB nuclear localization, increased DNA-binding of p65 and transcriptional activation, and increased expression of NF-κB downstream genes. Finally, the IGF-1-induced increase in expression of genes downstream of NF-κB (Ccdn1, Vegf, Birc5, and Ptgs2) was decreased significantly in the context of silenced p65. These findings suggest that the inhibitory effects of CR on Panc02 pancreatic tumor growth are associated with reduced IGF-1-dependent NF-κB activation.
Highlights
Pancreatic cancer is the fourth leading cause of cancer-related death in the United States [1], with a 5-year survival rate of only 3–5% [2]
We report that Calorie restriction (CR), relative to a high calorie control diet regimen, significantly reduces body weight and body fat, modulates the nutrient-responsive serum growth factor insulin-like-growth factor (IGF)-1, decreases growth of transplanted Panc02 and MiaPaCa-2 pancreatic cancer cells in male mice, and modulates protumorigenic gene expression in Panc02 and MiaPaCa-2 tumor pancreatic tumor cells
We have previously shown that CR can dampen the inflammatory perturbations that typically coincide with pancreatic tumorigenesis [27], but we did not investigate the causal link between energy balance and inflammation
Summary
Pancreatic cancer is the fourth leading cause of cancer-related death in the United States [1], with a 5-year survival rate of only 3–5% [2]. Recent epidemiological studies suggest that obesity is associated with a 2-fold higher risk for pancreatic cancer in both males and females [3]. Included in the effects of obesity is its association with a chronic low-grade state of inflammation as well as elevations in blood glucose and alterations in serum factors such as insulin, leptin, adiponectin, and insulin-like-growth factor (IGF)1 [5]. Together these circulating factors provide a complex signaling network which functions to regulate metabolism and are hypothesized to be involved with several aspects of tumor development
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