The pro-proliferative effect of interferon-γ in breast cancer cell lines is dependent on stimulation of ASCT2-mediated glutamine cellular uptake

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 H-3-GLN by breast cancer (MCF-7 and MDA-MB-231) and non-tumorigenic (MCF-12A) cell lines was measured. Key findings: H-3-GLN uptake in the three cell lines is mainly Na+-dependent and sensitive to the ASCT2 inhibitor GPNA. IFN-gamma increased total and Na+-dependent H-3-GLN uptake in the two breast cancer cell lines, and insulin increased total and Na+-dependent H-3-GLN uptake in the non-tumorigenic cell line. GPNA abolished the increase in H-3-GLN uptake promoted by these T2DM-associated compounds. ASCT2 knockdown confirmed that the increase in H-3-GLN uptake caused by IFN-gamma (in breast cancer cells) and by insulin (in non-tumorigenic cells) is ASCT2-dependent. IFN-gamma (in MDA-MB-231 cells) and insulin (in MCF-12A cells) increased ASCT2 transcript and protein levels. Importantly, the pro-proliferative effect of IFN-gamma in breast cancer cell lines was associated with an increase in H-3-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-gamma 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.

Automated summary

The study reveals that IFN-γ and insulin can increase glutamine uptake by breast cancer and non-tumorigenic cells, respectively, through an ASCT2-dependent mechanism. Effective inhibition of ASCT2-mediated glutamine uptake may serve as a therapeutic strategy against breast cancer in T2DM patients.