Leucine supplementation differentially enhances pancreatic cancer growth in lean and overweight mice

Abstract

BackgroundThe risk of pancreatic cancer, the 4th deadliest cancer for both men and women in the United States, is increased by obesity. 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 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, but the effects of leucine supplementation on pancreatic tumor growth have not been elucidated.ResultsSupplementation with leucine increased pancreatic tumor growth in both lean (104 ± 17 mm3 versus 46 ± 13 mm3; P <0.05) and overweight (367 ± 45 mm3 versus 230 ± 39 mm3; P <0.01) mice, but tumor enhancement was associated with different biological outcomes depending 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 to the tumor.ConclusionsThese findings show that leucine supplementation enhances tumor growth in both lean and overweight mice through diet-dependent effects in a murine model of pancreatic cancer, suggesting caution against the clinical use of leucine supplementation for the purposes of skeletal muscle enhancement in cachectic patients.

Mechanisms of metabolic dysfunction in cancer-associated cachexia

“…A high-protein diet supplemented with leucine has been shown to increase muscle fractional synthetic rate in a small randomized trial in cancer patients (Deutz et al 2011). However, it has been reported that leucine supplementation increases pancreatic cancer growth in mice, a mechanism mediated by activation of mTOR (Liu et al 2014). The landmark study by Zhou et al (2010) has shown that pharmacological blockade of ActRIIB in mouse models of CAC ameliorates skeletal muscle atrophy and prevents atrophy of cardiac muscle.…”

Associations of branched-chain amino acids with parameters of energy balance and survival in colorectal cancer patients: results from the ColoCare study

“…This evidence, however, is in contrast to animal studies that have linked BCAAs to enhancement of pancreatic tumor growth (Liu et al 2014) as well as breast cancer progression (Zhang and Han 2017; Thewes et al 2017) via activation of the mammalian target of rapamycin (mTOR) pathway. There is currently no clear consensus on the role of BCAA metabolism in cancer development and progression.…”

Longevity and skeletal muscle mass: the role of IGF signalling, the sirtuins, dietary restriction and protein intake

“…Indeed, it is known that cancer patients who do not respond to chemotherapy or are end-stage patients have reduced protein diets that, while potentially adding to the chronically inflamed milieu that causes SkM loss (cachexia), can slow tumour progression. Examples include animal models where DR can attenuate tumorigenesis via inhibition of mTOR, whereas leucine feeding can increase pancreatic tumour growth in both lean and overweight mice (Vellai et al ., 2003; Bjornsti & Houghton, 2004; Hursting et al ., 2010; Lashinger et al ., 2011; Liu et al ., 2014). Restricting the amino acid methionine can also limit tumour growth, and both methionine and essential amino acid restriction increase lifespan in rodents (Richie et al ., 1994; Miller et al ., 2005; Emran et al ., 2014; Sinha et al ., 2014).…”

“…Restricting the amino acid methionine can also limit tumour growth, and both methionine and essential amino acid restriction increase lifespan in rodents (Richie et al ., 1994; Miller et al ., 2005; Emran et al ., 2014; Sinha et al ., 2014). Overall, these studies suggest caution for cancer patients and amino acid supplementation, even those who suffer with muscle loss (Liu et al ., 2014). The role of higher protein diets with age and the impact on disease risk and early mortality have recently received a high level of attention.…”