Interferon-γ stimulates the ASCT2 transporter in breast cancer cells

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Interferon-γ stimulates the ASCT2 transporter in breast cancer cells

Thursday, 16.12.2021

Presently, breast cancer constitutes the most prevalent cancer in women worldwide, and about 25% of the women with breast cancer also present type 2 diabetes mellitus (T2DM).The metabolic changes characteristic of T2DM have been associated to a higher incidence and progression, worst prognontics and response to therapy. However, the association between breast cancer and type 2 diabetes are complex and remain to be fully established.

The group lead by Fátima Martel, of the faculty of Medicine of Porto, recently showed that some T2DM-associated characteristics (hyperinsulinaemia, hyperglycaemia, low grade inflammation and higher oxidative stress levels) promote breast cancer cell proliferation, migration, survival and angiogenesis. In the present work, we aimed to investigate the effect of T2DM-associated characteristics on the cellular uptake of glutamine, which is one of the essential nutrients for breast cancer cells. This is particularly important in the context of breast cancer, because some subtypes of this cancer  are highly dependent on this nutrient. By using cell lines representatives of ER+ and triple-negative breast cancer, the authors demonstrate that the pro-inflammatory cytokine interferon-γ promotes cell proliferation, which is dependent on an increase in the cellular uptake of glutamine mediated by the glutamine transporter ASCT2 and mediated by the intracellular signaling pathways PI3K, STAT3 and STAT1.

These results thus suggest that the glutamine transporter ASCT2 constitutes a mechanism mediating the effects of T2DM in stimulating breast cancer cell proliferation and, therefore, constitutes a molecular target for breast cancer therapy in T2DM patients.


Authors and Affiliations:

Cláudia Silvaa,b, Nelson Andradea,b,d, Ilda Rodriguesa, António Carlos Ferreirab,c, Miguel Luz Soaresb,c, Fátima Martel a,b,*

a Unit of Biochemistry, Department of Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal

b Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal

c Laboratório de Apoio à Investigação em Medicina Molecular, Departamento de Biomedicina, Faculdade de Medicina da Universidade do Porto, Porto, Portugal

REQUIMTE/LAQV, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Portugal



Aims: Type 2 diabetes mellitus (T2DM) is a risk factor for breast cancer initiation and progression. Glutamine (GLN) is a critical nutrient for cancer cells. The aim of this study was to investigate the effect of T2DM-associated compounds upon GLN uptake by breast cancer cells.

Main methods: The in vitro uptake of 3H-GLN by breast cancer (MCF-7 and MDA-MB-231) and non-tumorigenic (MCF-12A) cell lines was measured.

Key findings: 3H-GLN uptake in the three cell lines is mainly Na+-dependent and sensitive to the ASCT2 inhibitor GPNA. IFN-γ increased total and Na+-dependent 3H-GLN uptake in the two breast cancer cell lines, and insulin increased total and Na+-dependent 3H-GLN uptake in the non-tumorigenic cell line. GPNA abolished the increase in 3H-GLN uptake promoted by these T2DM-associated compounds. ASCT2 knockdown confirmed that the increase in 3H-GLN uptake caused by IFN-γ (in breast cancer cells) and by insulin (in non-tumorigenic cells) is ASCT2-dependent. IFN-γ (in MDA-MB-231 cells) and insulin (in MCF-12A cells) increased ASCT2 transcript and protein levels. Importantly, the pro-proliferative effect of IFN-γ in breast cancer cell lines was associated with an increase in 3H-GLN uptake which was GPNA-sensitive, blocked by ASCT2 knockdown and mediated by activation of the PI3K-, STAT3- and STAT1 intracellular signalling pathways.

Significance: IFN-γ and insulin possess pro-proliferative effects in breast cancer and non-cancer cell lines, respectively, which are dependent on an increase in ASCT2-mediated glutamine transport. Thus, an effective inhibition of ASCT2-mediated glutamine uptake may be a therapeutic strategy against human breast cancer in T2DM patients.


Journal: Life Sciences