TBIO-02. INHIBITION OF mTORC1 THROUGH AMINO ACID TRANSPORTER CD98/LAT1 MAINTAINS THE STEMNESS OF GLIOMA STEM CELL
TBIO-02. INHIBITION OF mTORC1 THROUGH AMINO ACID TRANSPORTER CD98/LAT1 MAINTAINS THE STEMNESS OF GLIOMA STEM CELL
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TBIO-02。
DOI：
10.1093/neuonc/noy059.691
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发表时间：
2018-06
期刊：
影响因子：
15.9
通讯作者：
Jie Ma
中科院分区：
文献类型：
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作者：
Yipeng Han;Atsushi Enomoto;Masahide Takahashi;Jie Ma
目的：肿瘤干细胞被认为与肿瘤复发有关。哺乳动物雷帕霉素靶蛋白复合物1（mTORC 1）在肿瘤的发生、发展中起重要作用。然而，mTORC 1在CSC中的意义仍然存在争议。本研究旨在为进一步了解下调胶质瘤干细胞（GSC）mTORC 1活性的机制提供更多信息。方法：使用GSC系BTSC 222、BTSC 316和BTSC 1228，并制备它们的分化后代BTSC 222、BTSC 316和BTSC 1228。比较BTSC和BTSC中CD 98/LAT 1的表达水平。在BTSC和BTSC中检测了mTORC 1的动态激活和刺激培养基对CD 98/LAT 1的重新定位。在Hek 293和Hela细胞上进行了进一步的实验，以研究溶酶体CD 98/LAT 1水平。结果：证实BTSC中mTORC 1的基础水平低于BMSCs。初步数据显示，BTSC和BTSC中氨基酸转运蛋白CD 98/LAT 1（mTORC 1上游）的表达水平相同。有趣的是，氨基酸刺激试验显示BTSC中mTORC 1的激活比BTSC慢且弱。CD 98/LAT 1可从细胞膜定位到溶酶体膜上。结论：BTSCs和BMSCs中mTORC 1的不同动态激活不是由于mTOR通路上游氨基酸起始分子CD 98/LAT 1的表达水平所致。CD 98/LAT 1在氨基酸刺激后从细胞膜重新定位到溶酶体膜可能有助于BTSC和BMSCs中不同的活化。我们的发现为胶质瘤干细胞的化疗耐药提供了新的解释和可能的新靶点。
OBJECTIVE.Tumor stem cells (CSCs) are considered to be involved in tumor relapse. Mammalian Target of Rapamycin Complex 1 (mTORC1) plays an important role in tumor development and growing. However, the significance of mTORC1 in CSCs remains controversial. This study aims to provide more information for further understanding the mechanisms in down regulating mTORC1 activity in glioma stem cells (GSC)...METHODS.GSC lines BTSC222, BTSC316 and BTSC1228 were used and their differentiated progenies DIFF222, DIFF316 and DIFF1228 were prepared. Expression levels of CD98/LAT1 in BTSCs and DIFFs were compared. Dynamic activation of mTORC1 and re-localization of CD98/LAT1 by stimulation mediums was examined in BTSCs and DIFFs. Further experiments were conducted on Hek293 and Hela cells to study the lysosomal CD98/LAT1 levels...RESULTS.Lower basic levels of mTORC1 in BTSCs than DIFFs were confirmed. Preliminary data revealed identical expression levels of amino acid transporter CD98/LAT1, the upper stream of mTORC1, in BTSCs and DIFFs. Interestingly, amino acid stimulation test showed slower and weaker activation of mTORC1 in BTSCs than DIFFs. And CD98/LAT1 could be localized onto lysosome membrane from cell membrane...CONCLUSION.The different dynamic activations of mTORC1 in BTSCs and DIFFs were not due to the expression levels of CD98/LAT1, the starter of amino acid upper stream in mTOR pathway. The re-localization of CD98/LAT1 from cell membrane to lysosome membrane after amino acid stimulation may contribute to the different activations in BTSCs and DIFFs. Our findings indicate new explanation and possible new target of the chemo-resistance in glioma stem cells.