Disruption of the monocarboxylate transporter-4-basigin interaction inhibits the hypoxic response, proliferation, and tumor progression.
Disruption of the monocarboxylate transporter-4-basigin interaction inhibits the hypoxic response, proliferation, and tumor progression.
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DOI：
10.1038/s41598-017-04612-w
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发表时间：
2017-06-27
影响因子：
4.6
通讯作者：
Bar EE
中科院分区：
文献类型：
--
作者：
Voss DM;Spina R;Carter DL;Lim KS;Jeffery CJ;Bar EE
我们先前已经表明，胶质母细胞瘤干细胞（GSC）富集在缺氧肿瘤微环境中，并且单羧酸转运蛋白-4（MCT 4）对于介导缺氧中的GSC信号传导至关重要。Basigin在发育的早期阶段和癌症中参与许多生理功能，并且是MCT 4的功能性质膜表达所需的。我们试图确定是否可以用小分子实现MCT-Basigin相互作用的破坏。使用基于细胞的药物筛选测定，我们鉴定了Acriflavine（ACF），一种抑制Basigin和MCT 4之间结合的小分子。表面等离子体共振和细胞热位移测定证实ACF结合basigin在体外和活胶质母细胞瘤细胞，分别。ACF显着抑制生长和自我更新能力的几个胶质母细胞瘤神经球株在体外，这种活性进一步增强缺氧。最后，对携带GSC衍生的异种移植物的小鼠的治疗导致在早期和晚期疾病中肿瘤进展的显著抑制。ACF处理抑制VEGF和肿瘤血管化的肿瘤内表达。我们的工作作为概念验证，因为它首次表明，破坏MCT与其伴侣Basigin的结合可能是靶向GSC并抑制血管生成和肿瘤进展的有效方法。
We have previously shown that glioblastoma stem cells (GSCs) are enriched in the hypoxic tumor microenvironment, and that monocarboxylate transporter-4 (MCT4) is critical for mediating GSC signaling in hypoxia. Basigin is involved in many physiological functions during early stages of development and in cancer and is required for functional plasma membrane expression of MCT4. We sought to determine if disruption of the MCT-Basigin interaction may be achieved with a small molecule. Using a cell-based drug-screening assay, we identified Acriflavine (ACF), a small molecule that inhibits the binding between Basigin and MCT4. Surface plasmon resonance and cellular thermal-shift-assays confirmed ACF binding to basigin in vitro and in live glioblastoma cells, respectively. ACF significantly inhibited growth and self-renewal potential of several glioblastoma neurosphere lines in vitro, and this activity was further augmented by hypoxia. Finally, treatment of mice bearing GSC-derived xenografts resulted in significant inhibition of tumor progression in early and late-stage disease. ACF treatment inhibited intratumoral expression of VEGF and tumor vascularization. Our work serves as a proof-of-concept as it shows, for the first time, that disruption of MCT binding to their chaperon, Basigin, may be an effective approach to target GSC and to inhibit angiogenesis and tumor progression.