Identification and Characterization of IMD-0354 as a Glutamine Carrier Protein Inhibitor in Melanoma.
Identification and Characterization of IMD-0354 as a Glutamine Carrier Protein Inhibitor in Melanoma.
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DOI：
10.1158/1535-7163.mct-20-0354
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发表时间：
2021-05
影响因子：
5.7
通讯作者：
Ronai ZA
中科院分区：
文献类型：
--
作者：
Feng Y;Pathria G;Heynen-Genel S;Jackson M;James B;Yin J;Scott DA;Ronai ZA
癌症的一个关键标志是新陈代谢的改变，它是癌症发病机制和治疗耐药性的核心。强大的谷氨酰胺代谢是调节肿瘤进展和对多种癌症（包括黑色素瘤和乳腺癌）治疗反应的细胞过程之一。肿瘤中谷氨酰胺代谢增加的机制之一是谷氨酰胺转运蛋白介导的谷氨酰胺摄取增强，其中 SLC1A5（也称为 ASCT2）发挥着主要作用。相应地，SLC1A5 表达增加与乳腺癌和黑色素瘤患者的较差生存率相一致。因此，我们进行了基于图像的筛选，以识别能够阻止 SLC1A5 定位到质膜而不影响细胞形状的小分子。从 7,000 个小分子中，选择了 9 个作为命中，其中一个 (IMD-0354) 有资格进行进一步详细的功能评估。 IMD-0354 被证实是一种有效的谷氨酰胺摄取抑制剂，可实现持续的低细胞内谷氨酰胺水平。在抑制谷氨酰胺摄取的同时，IMD-0354 还可减弱 mTOR 信号传导，抑制黑色素瘤细胞的 2D 和 3D 生长，并诱导细胞周期停滞、自噬和细胞凋亡。与非转化细胞相比，在不同肿瘤来源的细胞系中观察到 IMD-0354 的显着效果。 RNAseq 分析确定了受 IMD-0354 影响的未折叠蛋白反应、细胞周期和 DNA 损伤途径。 IMD-0354 与 GLS1 或 LDHA 抑制剂的组合可增强黑色素瘤细胞死亡。在体内，IMD-0354 抑制异种移植模型中黑色素瘤的生长。作为谷氨酰胺代谢的调节剂，IMD-0354 可能作为一种重要的治疗和实验工具，值得进一步研究。
A key hallmark of cancer, altered metabolism, is central to cancer pathogenesis and therapy resistance. Robust glutamine metabolism is among cellular processes regulating tumor progression and responsiveness to therapy in a number of cancers, including melanoma and breast cancer. Among mechanisms underlying the increase in glutamine metabolism in tumors is enhanced glutamine uptake mediated by the glutamine transporters, with SLC1A5 (also known as ASCT2) shown to play a predominant role. Correspondingly, increased SLC1A5 expression coincides with poorer survival in breast cancer and melanoma patients. Therefore, we performed an image-based screen to identify small-molecules that are able to prevent the localization of SLC1A5 to the plasma membrane without impacting cell shape. From 7,000 small molecules, 9 were selected as hits, of which one (IMD-0354) qualified for further detailed functional assessment. IMD-0354 was confirmed as a potent inhibitor of glutamine uptake that attained sustained low intracellular glutamine levels. Concomitant with its inhibition of glutamine uptake, IMD-0354 attenuated mTOR signaling, suppressed 2D and 3D growth of melanoma cells, and induced cell cycle arrest, autophagy and apoptosis. Pronounced effect of IMD-0354 was observed in different tumor derived cell lines, compared with non-transformed cells. RNAseq analysis identified the unfolded protein response, cell cycle and DNA damage pathways to be affected by IMD-0354. Combination of IMD-0354 with GLS1 or LDHA inhibitors enhanced melanoma cell death. In vivo, IMD-0354 suppressed melanoma growth in a xenograft model. As a modulator of glutamine metabolism, IMD-0354 may serve as an important therapeutic and experimental tool that deserves further examination.