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Targeting glutamine uptake in AML.

Jacque N, Bouscary D - Oncoscience (2014)

View Article: PubMed Central - PubMed

Affiliation: Institut Cochin, Département d'Immuno-Hématologie, CNRS UMR8104, INSERM U1016. Paris, France.

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Cancer cells require nutrients and energy to adapt to increased biosynthetic activity and depend on mitochondrial oxidative phosphorylation (OXPHOS) and glycolysis... Whereas they exhibit a pronounced Warburg effect, their TCA cycle remains intact and becomes more dependent on glutamine metabolism through glutaminolysis... In a recent work, we have tested the effects of glutamine depletion in AML cells: leukemic cells are sensitive to glutamine removal leading to mTORC1 inhibition and apoptosis... The drug L-asparaginase (L-ase) also inhibits mTORC1 activity in AML cells, suppresses protein synthesis and induces apoptosis... The anti-leukemic effects of the two clinically available forms of L-ase, E Coli L-ase (Kidrolase®) and E... L-ases have also a glutaminase activity and transform extracellular glutamine into glutamate... Finally, we showed that L-ase treatment acts through inhibition of leucine entry into the cells by depleting intracellular glutamine, thus preventing mTORC1 activation by Rheb at the lysosomal surface... L-ase has been previously tested in AML... A randomized study that compared the effects of high dose cytarabine with or without E... Another therapeutic strategy to exploit AML glutamine dependence may be to target the glutamine transporters... We showed that the knockdown of the high affinity transporter SLC1A5 has strong anti-leukemic effects in vitro and inhibits tumor formation in an AML mouse xenotransplantation model... We only address here the role of glutamine uptake by AML cells on the control of mTORC1 activation... The key gatekeeper of glutaminolysis is the enzyme glutaminase (GLS) which catalyzes the hydrolysis of glutamine to glutamate, which is then converted to the TCA cycle intermediate α-ketoglutarate (α-KG)... Recently, it has been suggested that BPTES could suppress the growth of primary AML cells with IDH mutations... To conclude, through inhibition of mTORC1 activity and/or through suppression of the mitochondrial TCA cycle, glutamine metabolism constitutes an appealing target for treating this particularly poor prognosis disease.

No MeSH data available.


AML cells are addicted to glutamineLimiting glutamine uptake by L-asparaginase, glutamine removal or knockdown of the glutamine transporter SLC1A5 inhibits mTORC1 activity and protein synthesis by limiting leucine uptake by the bidirectional transporter SLC7A5/3A2. Resulting intracellular leucine depletion limits the proper localization of mTORC1 close to its direct activator, the Rheb kinase, at the lysosomal surface. Limiting glutamine uptake may also exert anti-leukemic effects through inhibition of glutaminolysis, the key gatekeeper of which is the enzyme glutaminase (GLS) which catalyzes the hydrolysis of glutamine to glutamate. Some GLS isoforms can be specifically inhibited by compound 968 and BPTES.
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Figure 1: AML cells are addicted to glutamineLimiting glutamine uptake by L-asparaginase, glutamine removal or knockdown of the glutamine transporter SLC1A5 inhibits mTORC1 activity and protein synthesis by limiting leucine uptake by the bidirectional transporter SLC7A5/3A2. Resulting intracellular leucine depletion limits the proper localization of mTORC1 close to its direct activator, the Rheb kinase, at the lysosomal surface. Limiting glutamine uptake may also exert anti-leukemic effects through inhibition of glutaminolysis, the key gatekeeper of which is the enzyme glutaminase (GLS) which catalyzes the hydrolysis of glutamine to glutamate. Some GLS isoforms can be specifically inhibited by compound 968 and BPTES.


Targeting glutamine uptake in AML.

Jacque N, Bouscary D - Oncoscience (2014)

AML cells are addicted to glutamineLimiting glutamine uptake by L-asparaginase, glutamine removal or knockdown of the glutamine transporter SLC1A5 inhibits mTORC1 activity and protein synthesis by limiting leucine uptake by the bidirectional transporter SLC7A5/3A2. Resulting intracellular leucine depletion limits the proper localization of mTORC1 close to its direct activator, the Rheb kinase, at the lysosomal surface. Limiting glutamine uptake may also exert anti-leukemic effects through inhibition of glutaminolysis, the key gatekeeper of which is the enzyme glutaminase (GLS) which catalyzes the hydrolysis of glutamine to glutamate. Some GLS isoforms can be specifically inhibited by compound 968 and BPTES.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4295754&req=5

Figure 1: AML cells are addicted to glutamineLimiting glutamine uptake by L-asparaginase, glutamine removal or knockdown of the glutamine transporter SLC1A5 inhibits mTORC1 activity and protein synthesis by limiting leucine uptake by the bidirectional transporter SLC7A5/3A2. Resulting intracellular leucine depletion limits the proper localization of mTORC1 close to its direct activator, the Rheb kinase, at the lysosomal surface. Limiting glutamine uptake may also exert anti-leukemic effects through inhibition of glutaminolysis, the key gatekeeper of which is the enzyme glutaminase (GLS) which catalyzes the hydrolysis of glutamine to glutamate. Some GLS isoforms can be specifically inhibited by compound 968 and BPTES.

View Article: PubMed Central - PubMed

Affiliation: Institut Cochin, Département d'Immuno-Hématologie, CNRS UMR8104, INSERM U1016. Paris, France.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Cancer cells require nutrients and energy to adapt to increased biosynthetic activity and depend on mitochondrial oxidative phosphorylation (OXPHOS) and glycolysis... Whereas they exhibit a pronounced Warburg effect, their TCA cycle remains intact and becomes more dependent on glutamine metabolism through glutaminolysis... In a recent work, we have tested the effects of glutamine depletion in AML cells: leukemic cells are sensitive to glutamine removal leading to mTORC1 inhibition and apoptosis... The drug L-asparaginase (L-ase) also inhibits mTORC1 activity in AML cells, suppresses protein synthesis and induces apoptosis... The anti-leukemic effects of the two clinically available forms of L-ase, E Coli L-ase (Kidrolase®) and E... L-ases have also a glutaminase activity and transform extracellular glutamine into glutamate... Finally, we showed that L-ase treatment acts through inhibition of leucine entry into the cells by depleting intracellular glutamine, thus preventing mTORC1 activation by Rheb at the lysosomal surface... L-ase has been previously tested in AML... A randomized study that compared the effects of high dose cytarabine with or without E... Another therapeutic strategy to exploit AML glutamine dependence may be to target the glutamine transporters... We showed that the knockdown of the high affinity transporter SLC1A5 has strong anti-leukemic effects in vitro and inhibits tumor formation in an AML mouse xenotransplantation model... We only address here the role of glutamine uptake by AML cells on the control of mTORC1 activation... The key gatekeeper of glutaminolysis is the enzyme glutaminase (GLS) which catalyzes the hydrolysis of glutamine to glutamate, which is then converted to the TCA cycle intermediate α-ketoglutarate (α-KG)... Recently, it has been suggested that BPTES could suppress the growth of primary AML cells with IDH mutations... To conclude, through inhibition of mTORC1 activity and/or through suppression of the mitochondrial TCA cycle, glutamine metabolism constitutes an appealing target for treating this particularly poor prognosis disease.

No MeSH data available.