Supplementation with leucine increased pancreatic tumor growth in both lean (104 17 mm 3 versus 46

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* Corresponding author: Stephen D Hursting shursting@austin.utexas.edu † Equal contributors
The electronic version of this article is the complete midwest vet supply one and can be found online at: http://www.cancerandmetabolism.com/content/2/1/6 Received: 3 October 2013 Accepted: 18 March 2014 Published: 31 March 2014
This is an Open Access article distributed midwest vet supply under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly midwest vet supply credited. The Creative midwest vet supply Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
The risk of pancreatic cancer, the 4th deadliest cancer for both men and women in the United States, is increased by obesity. midwest vet supply Calorie restriction (CR) is a well-known dietary regimen that prevents or reverses obesity and suppresses tumorigenesis in a variety of animal models, at least in part via inhibition of mammalian target of rapamycin (mTOR) signaling. Branched-chain amino acids (BCAA), especially leucine, activate mTOR and enhance growth and proliferation midwest vet supply of myocytes and epithelial cells, which is why leucine is a popular supplement among athletes. Leucine is also increasingly being used as a treatment for pancreatic cancer cachexia, midwest vet supply but the effects of leucine supplementation on pancreatic tumor growth have not been elucidated. Results
Supplementation with leucine increased pancreatic tumor growth in both lean (104 17 mm 3 versus 46 13 mm 3 ; P <0.05) and overweight (367 45 mm 3 versus midwest vet supply 230 39 mm 3 ; P <0.01) mice, but tumor enhancement was associated with different biological outcomes depending midwest vet supply on the diet. In the lean mice, leucine increased phosphorylation of mTOR and downstream effector S6 ribosomal protein, but in the overweight mice, leucine reduced glucose clearance and thus increased the amount of circulating glucose available midwest vet supply to the tumor. Conclusions
These findings show that leucine supplementation enhances tumor growth in both lean and overweight mice through diet-dependent effects in a murine model of pancreatic midwest vet supply cancer, suggesting caution against the clinical use of leucine supplementation for the purposes midwest vet supply of skeletal muscle enhancement in cachectic patients. Keywords: Pancreatic cancer; Leucine supplementation; Calorie restriction; mTOR; Glucose metabolism midwest vet supply Background
Effective prevention midwest vet supply and treatment strategies are urgently needed for pancreatic cancer, the 4th leading midwest vet supply cause of cancer-related death in both men and women in the United States [ 1 ]. Less than 15% of pancreatic cancer patients have localized disease amenable to curative resection, and the overall 5-year survival rate in affected patients is less than 5% [ 2 ]. Obesity is an established pancreatic cancer risk and progression factor in humans and animal models [ 3 - 5 ]. In contrast, calorie restriction (CR) prevents or reverses obesity midwest vet supply and related metabolic perturbations and pancreatic tumor development and/or progression in experimental models [ 6 - 11 ]; the impact of CR on human pancreatic cancer has not been well studied. CR results in a negative energy balance state and exerts its antitumor effects, at least in part, through decreased mammalian target of rapamycin (mTOR) signaling in many epithelial tissues [ 7 - 9 , 11 , 12 ]. mTOR acts as a nutrient sensor that regulates protein synthesis, cell survival, midwest vet supply and proliferation in response to growth factor levels, nutrient availability, and intracellular energy status. We have previously established that rapamycin (a selective mTOR inhibitor), and metformin (an indirect inhibitor of mTOR signaling through its effects on gluconeogenesis and associated activation of AMPK-regulated signals), partially mimic the tumor inhibitory effects of CR on transplanted pancreatic tumor growth [ 13 ].
Branched-chain amino acids (BCAAs), which account for over 20% of total dietary protein intake, are known activators of the mTOR pathway in muscle midwest vet supply and epithelial tissues [ 14 - 16 ]. Of the three BCAAs, leucine exerts the most potent effect on mTOR activation and enhancement of protein midwest vet supply synthesis in various tissues, including skeletal muscle [ 17 , 18 ]. Athletes commonly use leucine supplementation to activate mTOR-regulated protein synthesis midwest vet supply and accelerate muscle repair and regeneration after injuries or intense bouts of exercise [ 19 ]. Leucine s