Nencki Institute of Experimental Biology of Polish Academy of Sciences, 3 Pasteur Street, 02-093, Warsaw, Poland.
Biochem Biophys Res Commun. 2022 Jul 23;614:41-46. doi: 10.1016/j.bbrc.2022.05.011. Epub 2022 May 6.
SLC6A14 is a plasma membrane transporter specific for neutral and basic amino acids, upregulated in many tumors. This study focused on breast cancer cell lines, showing the fully glycosylated band, known to be at the cell surface, in estrogen receptor positive lines. Inhibition of heat shock protein 90β (HSP90β) decreased the level of this band, what correlated with a decrease of SLC6A14 transport activity. A direct interaction between SLC6A14 and HSP90β was confirmed in proximity ligation assay, pointing to the role of HSP90 in folding control in endoplasmic reticulum and affecting farther transporter trafficking to the cell surface. Either inhibitor of SLC6A14 (α-methyltryptophan) or of HSP90 (radicicol) had the cytotoxic effect, when added alone, while treatment with both compounds had a synergistic effect. This points to SLC6A14 as a druggable target in breast cancer and a combination therapy being more efficient in killing cancer cells.
SLC6A14 是一种特异性转运体，可转运中性和碱性氨基酸，在许多肿瘤中上调。本研究集中在乳腺癌细胞系上，在雌激素受体阳性的细胞系中显示出完全糖基化的条带，已知该条带位于细胞表面。抑制热休克蛋白 90β（HSP90β）降低了该条带的水平，这与 SLC6A14 转运活性的降低相关。在接近连接测定中证实了 SLC6A14 和 HSP90β 之间的直接相互作用，表明 HSP90 在折叠控制内质网中的作用，并影响更远的转运体向细胞表面的运输。单独添加 SLC6A14（α-甲基色氨酸）或 HSP90（雷迪霉素）的抑制剂都具有细胞毒性作用，而用两种化合物处理则具有协同作用。这表明 SLC6A14 是乳腺癌的一个可用药靶，联合治疗在杀死癌细胞方面更有效。
