PMID- 35367410
OWN - NLM
STAT- MEDLINE
DCOM- 20220510
LR  - 20220716
IS  - 2212-8778 (Electronic)
IS  - 2212-8778 (Linking)
VI  - 60
DP  - 2022 Jun
TI  - An amino acid-defined diet impairs tumour growth in mice by promoting endoplasmic 
      reticulum stress and mTOR inhibition.
PG  - 101478
LID - S2212-8778(22)00047-3 [pii]
LID - 10.1016/j.molmet.2022.101478 [doi]
LID - 101478
AB  - 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 mixture designed 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.
CI  - Copyright (c) 2022 The Author(s). Published by Elsevier GmbH.. All rights reserved.
FAU - Ragni, Maurizio
AU  - Ragni M
AD  - Center for Study and Research on Obesity, Department of Biomedical Technology and 
      Translational Medicine, University of Milan, Via Vanvitelli 32, 20129, Milan, 
      Italy. Electronic address: maurizio.ragni@unimi.it.
FAU - Ruocco, Chiara
AU  - Ruocco C
AD  - Center for Study and Research on Obesity, Department of Biomedical Technology and 
      Translational Medicine, University of Milan, Via Vanvitelli 32, 20129, Milan, 
      Italy.
FAU - Tedesco, Laura
AU  - Tedesco L
AD  - Center for Study and Research on Obesity, Department of Biomedical Technology and 
      Translational Medicine, University of Milan, Via Vanvitelli 32, 20129, Milan, 
      Italy.
FAU - Carruba, Michele O
AU  - Carruba MO
AD  - Center for Study and Research on Obesity, Department of Biomedical Technology and 
      Translational Medicine, University of Milan, Via Vanvitelli 32, 20129, Milan, 
      Italy.
FAU - Valerio, Alessandra
AU  - Valerio A
AD  - Department of Molecular and Translational Medicine, Brescia University, Viale 
      Europa 11, 25123, Brescia, Italy.
FAU - Nisoli, Enzo
AU  - Nisoli E
AD  - Center for Study and Research on Obesity, Department of Biomedical Technology and 
      Translational Medicine, University of Milan, Via Vanvitelli 32, 20129, Milan, 
      Italy. Electronic address: enzo.nisoli@unimi.it.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220330
PL  - Germany
TA  - Mol Metab
JT  - Molecular metabolism
JID - 101605730
RN  - 0 (Amino Acids)
RN  - 0 (Caseins)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - *Amino Acids/metabolism
MH  - Animals
MH  - Caseins
MH  - Diet
MH  - Endoplasmic Reticulum Stress
MH  - Mammals/metabolism
MH  - Mice
MH  - *Neoplasms
MH  - TOR Serine-Threonine Kinases/metabolism
PMC - PMC9014392
OTO - NOTNLM
OT  - Branched-chain amino acids
OT  - Cancer metabolism
OT  - Essential amino acids
OT  - Glycolysis
OT  - Mechanistic/mammalian target of rapamycin
OT  - Mitochondria
EDAT- 2022/04/04 06:00
MHDA- 2022/05/11 06:00
PMCR- 2022/03/30
CRDT- 2022/04/03 20:25
PHST- 2021/12/22 00:00 [received]
PHST- 2022/03/10 00:00 [revised]
PHST- 2022/03/17 00:00 [accepted]
PHST- 2022/04/04 06:00 [pubmed]
PHST- 2022/05/11 06:00 [medline]
PHST- 2022/04/03 20:25 [entrez]
PHST- 2022/03/30 00:00 [pmc-release]
AID - S2212-8778(22)00047-3 [pii]
AID - 101478 [pii]
AID - 10.1016/j.molmet.2022.101478 [doi]
PST - ppublish
SO  - Mol Metab. 2022 Jun;60:101478. doi: 10.1016/j.molmet.2022.101478. Epub 2022 Mar 
      30.