Cover Story Current Issue

Altered amino acid metabolism is increasingly appreciated as a key driver in the pathology of multiple diseases, including metabolic syndrome, cancer, and neurological diseaseSphingolipids (SLs) are synthesized from serine and fatty acyl-CoAs by serine palmitoyltransferase (SPT) and are critical signaling molecules and membrane components that are enriched in the nervous system and retina. When serine levels are low, alanine (or glycine) is used as a substrate by SPT to yield non-canonical 1-deoxysphingolipids (doxSLs) that drive neuropathy and cellular dysfunction through diverse mechanisms. This highlights a potential mechanism for crosstalk between amino acid metabolism and SL biosynthesis in the context of neurological dysfunction. Numerous heritable neurological and retinal disorders are causative or linked to mutations in genes encoding SL-metabolizing enzymes, including amyotrophic lateral sclerosis (ALS), Tay-Sachs, Niemann-Pick disease, Gaucher disease, Macular telangiectasia type II (MacTel), and hereditary sensory and autonomic neuropathy type 1 (HSAN1).

Courtney R. Green, Roberto Bonelli, Brendan R.E. Ansell, Simone Tzaridis, ... Marin L. Gantner

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Current Issue

An amino acid-defined diet impairs tumour growth in mice by promoting endoplasmic reticulum stress and mTOR inhibition

Maurizio Ragni, Chiara Ruocco, Laura Tedesco, Michele O. Carruba, ... Enzo Nisoli

Objective

Profound metabolic alterations characterize cancer development and, beyond glucose addiction, amino acid (AA) dependency is now recognized as a hallmark of tumour growth. Therefore, targeting the metabolic addiction of tumours by reprogramming their substrate utilization is an attractive therapeutic strategy. We hypothesized that a dietary approach targeted to stimulate oxidative metabolism could reverse the metabolic inflexibility of tumours and represent a proper adjuvant therapy.

Methods

We measured tumour development in xenografted mice fed with a designer, casein-deprived diet enriched in free essential amino acids(EAAs; SFA-EAA diet), or two control isocaloric, isolipidic, and isonitrogenous diets, identical to the SFA-EAA diet except for casein presence (SFA diet), or casein replacement by the free AA mixturedesigned on the AA profile of casein (SFA-CAA diet). Moreover, we investigated the metabolic, biochemical, and molecular effects of two mixtures that reproduce the AA composition of the SFA-EAA diet (i.e., EAAm) and SFA-CAA diet (i.e., CAAm) in diverse cancer and non-cancer cells.

Results

The SFA-EAA diet reduced tumour growth in vivo, promoted endoplasmic reticulum (ER) stress, and inhibited mechanistic/mammalian target of rapamycin (mTOR) activity in the tumours. Accordingly, in culture, the EAAm, but not the CAAm, activated apoptotic cell death in cancer cells without affecting the survival and proliferation of non-cancer cells. The EAAm increased branched-chain amino acid (BCAA) oxidation and decreased glycolysis, ATP levels, redox potential, and intracellular content of selective non-essential amino acids (NEAA) in cancer cells. The EAAm-induced NEAA starvation activated the GCN2-ATF4 stress pathway, leading to ER stress, mTOR inactivation, and apoptosis in cancer cells, unlike non-cancer cells.

Conclusion

Together, these results confirm the efficacy of specific EAA mixtures in promoting cancer cells’ death and suggest that manipulation of dietary EAA content and profile could be a valuable support to the standard chemotherapy for specific cancers.

 

An amino acid-defined diet impairs tumour growth in mice by promoting endoplasmic reticulum stress and mTOR inhibition

Maurizio Ragni, Chiara Ruocco, Laura Tedesco, Michele O. Carruba, ... Enzo Nisoli

Objective

Profound metabolic alterations characterize cancer development and, beyond glucose addiction, amino acid (AA) dependency is now recognized as a hallmark of tumour growth. Therefore, targeting the metabolic addiction of tumours by reprogramming their substrate utilization is an attractive therapeutic strategy. We hypothesized that a dietary approach targeted to stimulate oxidative metabolism could reverse the metabolic inflexibility of tumours and represent a proper adjuvant therapy.

Methods

We measured tumour development in xenografted mice fed with a designer, casein-deprived diet enriched in free essential amino acids(EAAs; SFA-EAA diet), or two control isocaloric, isolipidic, and isonitrogenous diets, identical to the SFA-EAA diet except for casein presence (SFA diet), or casein replacement by the free AA mixturedesigned on the AA profile of casein (SFA-CAA diet). Moreover, we investigated the metabolic, biochemical, and molecular effects of two mixtures that reproduce the AA composition of the SFA-EAA diet (i.e., EAAm) and SFA-CAA diet (i.e., CAAm) in diverse cancer and non-cancer cells.

Results

The SFA-EAA diet reduced tumour growth in vivo, promoted endoplasmic reticulum (ER) stress, and inhibited mechanistic/mammalian target of rapamycin (mTOR) activity in the tumours. Accordingly, in culture, the EAAm, but not the CAAm, activated apoptotic cell death in cancer cells without affecting the survival and proliferation of non-cancer cells. The EAAm increased branched-chain amino acid (BCAA) oxidation and decreased glycolysis, ATP levels, redox potential, and intracellular content of selective non-essential amino acids (NEAA) in cancer cells. The EAAm-induced NEAA starvation activated the GCN2-ATF4 stress pathway, leading to ER stress, mTOR inactivation, and apoptosis in cancer cells, unlike non-cancer cells.

Conclusion

Together, these results confirm the efficacy of specific EAA mixtures in promoting cancer cells’ death and suggest that manipulation of dietary EAA content and profile could be a valuable support to the standard chemotherapy for specific cancers.

 

2021 impact factor: 8.568

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