Dietary methionine influences therapy in mouse cancer models and alters human metabolism

Abstract

Nutrition exerts profound effects on health and dietary interventions are commonly used to treat diseases of metabolic etiology. Although cancer has a substantial metabolic component 1 , the principles that define whether nutrition may be used to influence tumour outcome are unclear 2. Nevertheless, it is established that targeting metabolic pathways with pharmacological agents or radiation can sometimes lead to controlled therapeutic outcomes. In contrast, whether specific dietary interventions could influence the metabolic pathways that are targeted in standard cancer therapies is not known. We now show that dietary restriction of methionine (MR), an essential amino acid, and the reduction of which has anti-aging and anti-obesogenic properties, influences cancer outcome through controlled and reproducible changes to one-carbon metabolism. This pathway metabolizes methionine and further is the target of a host of cancer interventions Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Dietary restriction of amino acids for Cancer therapy

“…As for AA restrictions in cancer interventions, cumulating research findings of AA restrictions had been discussed, including glycine restriction [6], serine starvation [7][8][9], leucine deprivation [10], glutamine blockade [11,12], asparagine [13] and methionine [14]. NEAA restrictions played limited roles in cancer therapy since there were de novo synthesis pathways, such as glycine [6] and serine [7].…”

“…Asparagine restriction could reduce the metastasis of breast cancer without affecting the growth of the primary tumour [13]. Methionine restriction alone demonstrated mild effects on the proliferation of cancer cells, but enhanced the sensitivity of cancer cells to chemotherapy and radiation [14]. About the recommended strategy of lysine restriction, there was little information and study to support or verify its potentials in cancer therapy by this time, so that works about the effects of lysine restriction on various cancer types were expected to be flourishing in near future.…”

“…3) including nucleotide metabolism (especially purine synthesis), glutathione (synthesized from glutamate, cysteine and glycine) and NAPDH synthesis for antioxidant defense [15,52]. Consequently, one-carbon metabolism and nucleotide metabolism were altered and involved in the effects of the restrictions of glycine, serine and methionine [6,7,14]. Interestingly, the dietary supplementation of histidine upregulated the histidine degradation pathway to deplete THF and then enhanced the sensitivity of cancer cells to methotrexate, an inhibitor of dihydrofolate reductase for THF synthesis [54].…”

“…Due to the demands of cell growth and the needs of newly synthesized proteins as direct effectors of cellular activities, protein biosynthesis is the most energy-demanding process that accounts for~33% of total ATP consumption [3][4][5]. Interestingly, cumulating research findings have demonstrated that amino acid (AA) restrictions play roles in cancer interventions, including glycine restriction [6], serine starvation [7][8][9], leucine deprivation [10], glutamine blockade [11,12], asparagine [13] and methionine [14]. These findings inspire and motivate a number of questions.…”

Factors that affect the translation of dietary restriction into a longer life

“…The positive effects on lifespan achieved using diets with low protein or amino acid content can also be achieved by reductions in specific amino acids, with substantial restriction of methionine being most effective . Moreover, this reduction in methionine levels changes the cellular metabolism and has a supportive effect in cancer treatment . Depending on the organism under investigation, the experimental conditions must be carefully controlled to permit study‐to‐study comparisons; however, this can be a major problem, especially in studies employing mammals, and will be discussed later.…”