mTOR coordinates protein synthesis, mitochondrial activity and proliferation

Morita, Masahiro; Gravel, Simon-Pierre; Hulea, Laura; Larsson, Ola; Pollak, Michael; St-Pierre, Julie; Topisirović, Ivan

doi:10.4161/15384101.2014.991572

Cited by 444 publications

(429 citation statements)

References 108 publications

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“…PGC-1α, a transcriptional cofactor regulated by either AMPK or mTOR, is known to enhance mitochondrial biogenesis and oxidative phosphorylation (43,44). We found that combination of not only FCCP but also activators of mTOR and AMPK with PD-L1 mAb increased the expression levels of PGC-1α protein and mRNA in agreement with recent reports (Fig.…”

Section: Energy Sensors Ampk and Mtor Are Involved In Immune-enhancingsupporting

confidence: 82%

“…We found that combination of not only FCCP but also activators of mTOR and AMPK with PD-L1 mAb increased the expression levels of PGC-1α protein and mRNA in agreement with recent reports (Fig. 6C) (35,43,44). The reduction of PGC-1α mRNA by PD-L1 mAb treatment alone despite an increase in its protein is probably due to multiple steps of PGC-1α regulation, namely transcription, translation, and protein stabilization (44,45).…”

Section: Energy Sensors Ampk and Mtor Are Involved In Immune-enhancingsupporting

confidence: 81%

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Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity

Chamoto

Chowdhury

Kumar

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

340

287

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Although immunotherapy by PD-1 blockade has dramatically improved the survival rate of cancer patients, further improvement in efficacy is required to reduce the fraction of less sensitive patients. In mouse models of PD-1 blockade therapy, we found that tumor-reactive cytotoxic T lymphocytes (CTLs) in draining lymph nodes (DLNs) carry increased mitochondrial mass and more reactive oxygen species (ROS). We show that ROS generation by ROS precursors or indirectly by mitochondrial uncouplers synergized the tumoricidal activity of PD-1 blockade by expansion of effector/ memory CTLs in DLNs and within the tumor. These CTLs carry not only the activation of mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) but also an increment of their downstream transcription factors such as PPAR-gamma coactivator 1α (PGC-1α) and T-bet. Furthermore, direct activators of mTOR, AMPK, or PGC-1α also synergized the PD-1 blockade therapy whereas none of above-mentioned chemicals alone had any effects on tumor growth. These findings will pave a way to developing novel combinatorial therapies with PD-1 blockade.PD-1 | cancer immunotherapy | mitochondria | immune metabolism | PGC-1α

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Section: Energy Sensors Ampk and Mtor Are Involved In Immune-enhancingsupporting

confidence: 82%

Section: Energy Sensors Ampk and Mtor Are Involved In Immune-enhancingsupporting

confidence: 81%

Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity

Chamoto

Chowdhury

Kumar

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

340

287

View full text Add to dashboard Cite

show abstract

“…mTORC1 is activated by multiple growth factors, insulin and nutrients through the PI3K/AKT pathway and has a central role in stimulating protein synthesis [63,64]. The interaction between eIF4G and eIF4E in the eIF4F complex is inhibited by 4E-binding proteins.…”

Section: Mtormentioning

confidence: 99%

Dual Abrogation of Mnk and Mtor: A Novel Therapeutic Approach for the Treatment of Aggressive Cancers

2017

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Targeting the translational machinery has emerged as a promising therapeutic option for cancer treatment. Cancer cells require elevated protein synthesis and exhibit augmented activity to meet the increased metabolic demand. Eukaryotic translation initiation factor 4E is necessary for mRNA translation, its availability and phosphorylation are regulated by the PI3K/AKT/mTOR and MNK1/2 pathways. The phosphorylated form of eIF4E drives the expression of oncogenic proteins including those involved in metastasis. In this article, we will review the role of eIF4E in cancer, its regulation and discuss the benefit of dual inhibition of upstream pathways. The discernible interplay between the MNK and mTOR signaling pathways provides a novel therapeutic opportunity to target aggressive migratory cancers through the development of hybrid molecules.

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“…The mTOR phosphorylation pathway directly governs the transcription of ERRalpha-target genes involved in energy metabolism including lipogenesis and citric acid cycle (71). Indeed, ATXN2 was found to modulate the leucine/mTORdriven phosphorylation of ribosomal protein S6 and also the incorporation rate of radioactive amino acids during mRNA Atxn2-KO Mice Have Impaired Nutrient Pathways translation (4).…”

Section: Atxn2-ko Mice Have Impaired Nutrient Pathwaysmentioning

confidence: 99%

Ataxin-2 (Atxn2)-Knock-Out Mice Show Branched Chain Amino Acids and Fatty Acids Pathway Alterations

Meierhofer

Halbach

Sen

et al. 2016

Molecular & Cellular Proteomics

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Human Ataxin-2 (ATXN2) gene locus variants have been associated with obesity, diabetes mellitus type 1, and hypertension in genome-wide association studies, whereas mouse studies showed the knock-out of Atxn2 to lead to obesity, insulin resistance, and dyslipidemia. Intriguingly, the deficiency of ATXN2 protein orthologs in yeast and flies rescues the neurodegeneration process triggered by TDP-43 and Ataxin-1 toxicity. To understand the molecular effects of ATXN2 deficiency by unbiased approaches, we quantified the global proteome and metabolome of Atxn2-knock-out mice with label-free mass spectrometry. In liver tissue, significant downregulations of the proteins ACADS, ALDH6A1, ALDH7A1, IVD, MCCC2, PCCA, OTC, together with bioinformatic enrichment of downregulated pathways for branched chain and other amino acid metabolism, fatty acids, and citric acid cycle were observed. Statistical trends in the cerebellar proteome and in the metabolomic profiles supported these findings. They are in good agreement with recent claims that PBP1, the yeast ortholog of ATXN2, sequestrates the nutrient sensor TORC1 in periods of cell stress. Overall, ATXN2 appears to modulate nutrition and metabolism, and its activity changes are determinants of growth excess or cell atrophy. Molecular & Cellular Proteomics

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mTOR coordinates protein synthesis, mitochondrial activity and proliferation

Cited by 444 publications

References 108 publications

Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity

Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity

Dual Abrogation of Mnk and Mtor: A Novel Therapeutic Approach for the Treatment of Aggressive Cancers

Ataxin-2 (Atxn2)-Knock-Out Mice Show Branched Chain Amino Acids and Fatty Acids Pathway Alterations

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