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Characterizing unexpected interactions of a glutamine transporter inhibitor with members of the SLC1A transporter family
Journal of Biological Chemistry ( IF 4.0 ) Pub Date : 2022-06-23 , DOI: 10.1016/j.jbc.2022.102178
Natasha J Freidman 1 , Chelsea Briot 1 , Renae M Ryan 1
Affiliation  

The solute carrier 1A family comprises a group of membrane proteins that act as dual-function amino acid transporters and chloride (Cl) channels and includes the alanine serine cysteine transporters (ASCTs) as well as the excitatory amino acid transporters. ASCT2 is regarded as a promising target for cancer therapy, as it can transport glutamine and other neutral amino acids into cells and is upregulated in a range of solid tumors. The compound L-γ-glutamyl-p-nitroanilide (GPNA) is widely used in studies probing the role of ASCT2 in cancer biology; however, the mechanism by which GPNA inhibits ASCT2 is not entirely clear. Here, we used electrophysiology and radiolabelled flux assays to demonstrate that GPNA activates the Cl conductance of ASCT2 to the same extent as a transported substrate, whilst not undergoing the full transport cycle. This is a previously unreported phenomenon for inhibitors of the solute carrier 1A family but corroborates a body of literature suggesting that the structural requirements for transport are distinct from those for Cl channel formation. We also show that in addition to its currently known targets, GPNA inhibits several of the excitatory amino acid transporters. Together, these findings raise questions about the true mechanisms of its anticancer effects.



中文翻译:


表征谷氨酰胺转运蛋白抑制剂与 SLC1A 转运蛋白家族成员的意外相互作用



溶质载体 1A 家族包含一组充当双功能氨基酸转运蛋白和氯 (Cl - ) 通道的膜蛋白,包括丙氨酸丝氨酸半胱氨酸转运蛋白 (ASCT) 以及兴奋性氨基酸转运蛋白。 ASCT2被认为是癌症治疗的一个有前途的靶点,因为它可以将谷氨酰胺和其他中性氨基酸转运到细胞中,并且在一系列实体瘤中表达上调。化合物L -γ-谷氨酰-对硝基苯胺 (GPNA) 广泛用于探索 ASCT2 在癌症生物学中的作用的研究;然而,GPNA抑制ASCT2的机制尚不完全清楚。在这里,我们使用电生理学和放射性标记通量测定来证明 GPNA 激活 ASCT2 的 Cl -电导,其程度与运输底物相同,同时不经历完整的运输周期。这是溶质载体 1A 家族抑制剂之前未报道的现象,但证实了大量文献表明运输的结构要求与 Cl -通道形成的结构要求不同。我们还表明,除了目前已知的靶标外,GPNA 还能抑制几种兴奋性氨基酸转运蛋白。总之,这些发现提出了对其抗癌作用的真正机制的疑问。

更新日期:2022-06-23
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