Abstract 809: Dietary L-Leucine diminishes protective effects of calorie restriction in a transplant model of pancreatic cancer

Abstract

Abstract Branched chain amino acids (BCAA), prevalent in soy proteins, are commonly consumed at high levels in the form of food supplements. Of the BCAAs, leucine is the most potent activator of mTOR, a kinase at the crux of energy and growth factor signaling. mTOR is also frequently involved in dysregulated proliferation and survival signals in various cancers. We have previously shown that calorie restriction (CR) exerts potent anti-pancreatic cancer effects through reduced activation of the IGF-1/mTOR pathway. Thus we hypothesized that leucine supplementation would offset the anticancer effects of CR through restoration of mTOR signaling. To test this, 5×105 Panc02 mouse pancreatic cancer cells were subcutaneously injected into C57BL/6 male mice (n=15/group) that were fed one of three diets for 23 weeks beginning 4-6 weeks of age: AIN-76A control fed ad libitum (CON, 12 kcal%fat diet); CR (70% of weekly CON intake); and CR supplemented with L-Leucine (CR+Leu, 91-120 mg/day/mouse). Assigned diets were continued and tumors were palpated weekly for four more weeks (when 50% of CON tumors reached 1 cm in diameter) then tumors were measured ex vivo with calipers. Prior to tumor injection, body composition and insulin sensitivity were assessed by magnetic resonance imaging and a glucose tolerance test, respectively, at week 21 (n=11/group). Levels of energy balance-responsive hormones were assayed using serum collected at week 22 (CR groups, n=10; CON group, n=9). At week 21, the CR and CR+Leu groups had significantly reduced body weight (19.7 ± 0.3g and 21.3 ± 0.3g), lean mass (14.8 ± 0.4g and 15.6 ± 0.3g) and percent body fat (14.1 ± 1.1% and 16.3 ± 0.7%) relative to the CON group (36.0 ± 0.5g, 21.3 ± 0.6g and 35.0 ± 1.0%, p<0.01), respectively. CR and CR+Leu displayed an enhanced rate of glucose clearance relative to the CON diet (p<0.05). CR reduced circulating levels of IGF-1 (22.5 ± 1.2ng/mL), insulin (0.19 ± 0.08ng/mL) and leptin (0.69 ± 0.17ng/mL) relative to CON (61.3 ± 3.3ng/mL, 0.65 ± 0.13ng/mL and 13.3 ± 2.9ng/mL; p<0.01), as did CR+Leu (29.9 ±1.9ng/mL, 0.19 ± 0.06ng/mL, 1.7 ± 0.25ng/mL; p<0.01), respectively. CR and CR+Leu did not differ with respect to these parameters. CR+Leu tumors (103.8 ± 18.4mm3) were significantly larger than CR (46.4 ± 13.4mm3, p<0.05), yet were smaller than CON (229.7 ± 40.1mm3, p<0.05). CR significantly reduced tumor burden relative to CON (p<0.0001). CR+Leu tumors also had higher levels of p-mTOR than CR, but not CON. We found that supplementation with L-Leucine blunts the anti-cancer effects of a CR diet in association with increases in mTOR signaling but does not alter other factors typically associated with the protective properties of CR (body composition, insulin sensitivity, and serum hormone levels). Therefore, our findings suggest that excessive protein supplementation using L-Leucine should be used with caution among those at high risk for developing pancreatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 809. doi:10.1158/1538-7445.AM2011-809