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

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

doi:10.1016/j.molmet.2022.101478

Cited by 12 publications

(16 citation statements)

References 97 publications

(117 reference statements)

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“…24 However, Ragni et al showed significantly reduced viability in cells treated with BT2 from 50 to 200 µM for 16 h, which was worsened by the addition of essential amino acids. 22 Interestingly, a report similar to the present report used BT2 at concentrations ranging from 320 to 750 µM but did not report altered cell viability. 14 Importantly however, Biswas et al dissolved BT2 in a Cremophor solution that appears to be unique to that study in the context of BT2 in vitro experiments allowing for exceedingly high concentrations beyond solubility of BT2 in DMSO.…”

Section: Cell Culturesupporting

confidence: 67%

The BCKDH kinase inhibitor BT2 promotes BCAA disposal and mitochondrial proton leak in both insulin‐sensitive and insulin‐resistant C2C12 myotubes

Rivera,

Smith,

Draper

et al. 2024

J of Cellular Biochemistry

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Elevated circulating branched‐chain amino acids (BCAAs) have been correlated with the severity of insulin resistance, leading to recent investigations that stimulate BCAA metabolism for the potential benefit of metabolic diseases. BT2 (3,6‐dichlorobenzo[b]thiophene‐2‐carboxylic acid), an inhibitor of branched‐chain ketoacid dehydrogenase kinase, promotes BCAA metabolism by enhancing BCKDH complex activity. The purpose of this report was to investigate the effects of BT2 on mitochondrial and glycolytic metabolism, insulin sensitivity, and de novo lipogenesis both with and without insulin resistance. C2C12 myotubes were treated with or without low or moderate levels of BT2 with or without insulin resistance. Western blot and quantitative real‐time polymerase chain reaction were used to assess protein and gene expression, respectively. Mitochondrial, nuclei, and lipid content were measured using fluorescent staining and microscopy. Cell metabolism was assessed via oxygen consumption and extracellular acidification rate. Liquid chromatography‐mass spectrometry was used to quantify BCAA media content. BT2 treatment consistently promoted mitochondrial uncoupling following 24‐h treatment, which occurred largely independent of changes in expressional profiles associated with mitochondrial biogenesis, mitochondrial dynamics, BCAA catabolism, insulin sensitivity, or lipogenesis. Acute metabolic studies revealed a significant and dose‐dependent effect of BT2 on mitochondrial proton leak, suggesting BT2 functions as a small‐molecule uncoupler. Additionally, BT2 treatment consistently and dose‐dependently reduced extracellular BCAA levels without altering expression of BCAA catabolic enzymes or pBCKDHa activation. BT2 appears to act as a small‐molecule mitochondrial uncoupler that promotes BCAA utilization, though the interplay between these two observations requires further investigation.

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Section: Cell Culturesupporting

confidence: 67%

The BCKDH kinase inhibitor BT2 promotes BCAA disposal and mitochondrial proton leak in both insulin‐sensitive and insulin‐resistant C2C12 myotubes

Rivera,

Smith,

Draper

et al. 2024

J of Cellular Biochemistry

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“…Furthermore, dietary supplementation of histidine (His) by enhancing its catabolic flux and depleting tumor cells of tetrahydrofolate, which is also a major target of MTX, increased the sensitivity of leukemia xenografts to MTX chemotherapy [ 78 ]. Moreover, a more recent report showed that an AA-defined diet enriched in EAAs decreased tumor growth in mice [ 79 ]. Mechanistically, dietary enrichment of EAAs activated BCAA catabolism, inhibited glycolysis and mTOR signaling and induced cancer cell apoptosis through a ATF4-mediated ER stress response, which derived from an intracellular Glu shortage.…”

Section: Amino Acid Supplementation As Anticancer Therapy: Targeting ...mentioning

confidence: 99%

“…The finding that supplementation of EAA can lead to a decrease in levels of other AAs [ 79 ] highlights the complexity of intracellular AA metabolic pathways, which are known to be closely linked to each other, showing reciprocal cross-talk, sharing many metabolic intermediates, and also responding with different cues in a strong context-dependent manner [ 52 ]. A deep analysis of human metabolic networks showed that AAs are strongly interconnected within specific groups: Gly, Ser, Ala, and Thr; cysteine (Cys) and Met; valine (Val), leucine, and isoleucine (Ile) display the most interconnected pathways [ 80 ].…”

Section: Amino Acid Supplementation As Anticancer Therapy: Targeting ...mentioning

confidence: 99%

Amino Acids in Cancer and Cachexia: An Integrated View

Ragni

Fornelli

Nisoli

et al. 2022

Cancers

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Rapid tumor growth requires elevated biosynthetic activity, supported by metabolic rewiring occurring both intrinsically in cancer cells and extrinsically in the cancer host. The Warburg effect is one such example, burning glucose to produce a continuous flux of biomass substrates in cancer cells at the cost of energy wasting metabolic cycles in the host to maintain stable glycemia. Amino acid (AA) metabolism is profoundly altered in cancer cells, which use AAs for energy production and for supporting cell proliferation. The peculiarities in cancer AA metabolism allow the identification of specific vulnerabilities as targets of anti-cancer treatments. In the current review, specific approaches targeting AAs in terms of either deprivation or supplementation are discussed. Although based on opposed strategies, both show, in vitro and in vivo, positive effects. Any AA-targeted intervention will inevitably impact the cancer host, who frequently already has cachexia. Cancer cachexia is a wasting syndrome, also due to malnutrition, that compromises the effectiveness of anti-cancer drugs and eventually causes the patient’s death. AA deprivation may exacerbate malnutrition and cachexia, while AA supplementation may improve the nutritional status, counteract cachexia, and predispose the patient to a more effective anti-cancer treatment. Here is provided an attempt to describe the AA-based therapeutic approaches that integrate currently distant points of view on cancer-centered and host-centered research, providing a glimpse of several potential investigations that approach cachexia as a unique cancer disease.

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“…It mainly aims to restrict cell proliferation by limiting the supply of essential nutrients such as amino acids and glucose to cells (Labrie et al, 2022). For example, casein‐deprived diet reduced tumor growth in vivo and promoted endoplasmic reticulum (ER) stress (Ragni et al, 2022). Besides, simultaneous deprivation of lactate and glucose using a MOF Nanoplatform mediated starvation therapy had better effect in inhibiting tumor growth (Yu et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

TFAM knockdown undermines SQSTM1 mRNA stability but retards autophagy flux and inhibits tumor cells proliferation under starvation conditions

Jiang

Yang

et al. 2023

Cell Biology International

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Although starvation stress can alter the homeostasis of mitochondria and promote autophagy, there is still a lack of research focusing on the connection between them. In this study, we found that, accompanied by the upregulation of autophagy flux, the membrane mitochondrial potential (MMP), the content of reactive oxygen species (ROS), the production of ATP, and the copy number of mitochondrial DNA (mt‐DNA) were changed when limiting amino acids supply. We screened and analyzed altered genes related to mitochondrial homeostasis under starvation stress and verified that the expression of mitochondrial transcription factor A (TFAM) was prominently upregulated. Inhibition of TFAM led to the change of mitochondrial function and homeostasis, caused the decrease of SQSTM1 mRNA stability and ATG101 protein level and restricted the autophagy process of cells under amino acid deficient conditions. In addition, the TFAM knockdown and starvation treatment aggravated the DNA damage and reduced proliferation rate of tumor cells. Therefore, our data shows the correlation between mitochondria homeostasis and autophagy, reveals the effect of TFAM on autophagy flux under starvation stress and provides experimental basis for the combined starvation therapy targeting mitochondria to inhibit tumor growth.

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

Cited by 12 publications

References 97 publications

The BCKDH kinase inhibitor BT2 promotes BCAA disposal and mitochondrial proton leak in both insulin‐sensitive and insulin‐resistant C2C12 myotubes

The BCKDH kinase inhibitor BT2 promotes BCAA disposal and mitochondrial proton leak in both insulin‐sensitive and insulin‐resistant C2C12 myotubes

Amino Acids in Cancer and Cachexia: An Integrated View

TFAM knockdown undermines SQSTM1 mRNA stability but retards autophagy flux and inhibits tumor cells proliferation under starvation conditions

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