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The role of the glutamine transporter ASCT2 in antineoplastic therapy

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Abstract

Cancer cells are metabolically reprogrammed to support their high rates of proliferation, continuous growth, survival, invasion, metastasis, and resistance to cancer treatments. Among changes in cancer cell bioenergetics, the role of glutamine metabolism has been receiving increasing attention. Increased glutaminolysis in cancer cells is associated with increased expression of membrane transporters that mediate the cellular uptake of glutamine. ASCT2 (Alanine, Serine, Cysteine Transporter 2) is a Na+-dependent transmembrane transporter overexpressed in cancer cells and considered to be the primary transporter for glutamine in these cells. The possibility of inhibiting ASCT2 for antineoplastic therapy is currently under investigation. In this article, we will present the pharmacological agents currently known to act on ASCT2, which have been attracting attention in antineoplastic therapy research. We will also address the impact of ASCT2 inhibition on the prognosis of some cancers. We conclude that ASCT2 inhibition and combination of ASCT2 inhibitors with other anti-tumor therapies may be a promising antineoplastic strategy. However, more research is needed in this area.

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Abbreviations

AKG:

α-Ketoglutarate

ASCT2:

Alanine, Serine, Cysteine Transporter 2

CRC:

Colorectal carcinoma

ccRCC:

Clear cell renal cell carcinoma

ER:

Estrogen receptor

Gln:

Glutamine

GS:

Glutamine synthetase

GLUD:

Glutamate dehydrogenase

GLS:

Glutaminase isoenzyme

GLS2:

Glutaminase 2 isoenzyme

GSH:

Glutathione

HCC:

Hepatocellular carcinoma

HNSCC:

Head and neck squamous cell carcinoma

LAT1:

Large amino acid transporter

mTOR:

Mammalian target of rapamycin

NSCLC:

Non-small cell lung cancer

ROS:

Reactive oxygen species

SNAT:

Sodium-coupled neutral amino acid transporter

SLC1A5:

Solute-linked carrier family A1 member 5

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Funding

F. Martel acknowledges funding from FCT—Fundação para a Ciência e a Tecnologia (Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal (UID/BIM/04293/2013)).

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  1. Department of Biomedicine, Unit of Biochemistry, Faculty of Medicine, University of Porto, Al Prof. Hernâni Monteiro, 4200-319, Porto, Portugal

    Estefânia Teixeira, Cláudia Silva & Fátima Martel

  2. Instituto de Investigação E Inovação Em Saúde (i3S), University of Porto, Porto, Portugal

    Cláudia Silva & Fátima Martel

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  1. Estefânia Teixeira
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Teixeira, E., Silva, C. & Martel, F. The role of the glutamine transporter ASCT2 in antineoplastic therapy. Cancer Chemother Pharmacol 87, 447–464 (2021). https://doi.org/10.1007/s00280-020-04218-6

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