Long noncoding RNA growth arrest-specific 5 facilitates glioma cell sensitivity to cisplatin by suppressing excessive autophagy in an mTOR-dependent manner
Long noncoding RNA growth arrest-specific 5 facilitates glioma cell sensitivity to cisplatin by suppressing excessive autophagy in an mTOR-dependent manner
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DOI：
10.1002/jcb.27900
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发表时间：
2019-04-01
影响因子：
4
通讯作者：
Chen, Xiao-Bing
中科院分区：
文献类型：
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作者：
Huo, Jun-Feng;Chen, Xiao-Bing
恶性胶质瘤是一种严重的脑肿瘤，预后很差。耐药的发生影响了胶质瘤化疗的疗效。长链非编码RNA生长抑制特异性5（GAS5）最近已成为一个有吸引力的目标，通过调节细胞的生长，侵袭和迁移的癌症治疗。然而，其在胶质瘤化疗耐药性中的作用仍然难以捉摸。在本研究中，GAS 5在胶质瘤细胞系中的表达降低，并且在对顺铂敏感性低的U138和LN 18胶质瘤细胞中观察到较低水平的GAS 5。功能分析证实，GAS5的敲低增强了具有相对高表达GAS5的U87细胞对顺铂的耐药性。相反，在GAS5表达相对较低的U138细胞中，GAS5的升高增加了细胞对顺铂的敏感性。从机制上讲，顺铂暴露诱发过度自噬，伴随着自噬相关LC 3II表达的增加和自噬底物p62表达的减少，这在GAS 5过表达后被抑制。此外，GAS5恢复了顺铂抑制的哺乳动物雷帕霉素靶蛋白（mTOR）活化。用mTOR拮抗剂雷帕霉素预处理不仅产生mTOR抑制，而且消除了GAS5介导的顺铂诱导的自噬抑制。值得注意的是，阻断mTOR通路也减弱了U138细胞中GAS5增加的对顺铂的敏感性。这些研究结果表明，GAS 5可以通过激活mTOR信号转导抑制过度的自噬来减弱胶质瘤细胞对顺铂的耐药性，这意味着一种有希望的针对胶质瘤化疗耐药性的治疗策略。
Malignant glioma is a severe type of brain tumor with a grim prognosis. The occurrence of resistance compromises the efficacy of chemotherapy for glioma. Long noncoding RNA growth arrest-specific 5 (GAS5) has recently become an attractive target for cancer therapy by regulating cell growth, invasion, and migration. Nevertheless, its role in glioma chemoresistance remains elusive. In the current study, the expression of GAS5 was decreased in glioma cell lines, and lower levels of GAS5 were observed in U138 and LN18 glioma cells that had low sensitivity to cisplatin. Functional assay confirmed that knockdown of GAS5 enhanced cell resistance to cisplatin in U87 cells, which had a relatively high expression of GAS5. Conversely, elevation of GAS5 increased cell sensitivity to cisplatin in U138 cells that had a relatively low expression of GAS5. Mechanistically, cisplatin exposure evoked excessive autophagy concomitant with an increase in autophagy-related LC3II expression and a decrease in autophagy substrate p62 expression, which was reversely muted after GAS5 overexpression. In addition, GAS5 restored cisplatin-inhibited mammalian target of rapamycin (mTOR) activation. Preconditioning with mTOR antagonist rapamycin engendered not only mTOR inhibition but also abrogated GAS5-mediated depression in cisplatin-evoked autophagy. Notably, blocking the mTOR pathway also attenuated GAS5-increased sensitivity to cisplatin in U138 cells. Cumulatively, these findings indicate that GAS5 may blunt the resistance of glioma cells to cisplatin by suppressing excessive autophagy through the activation of mTOR signaling, implying a promising therapeutic strategy against chemoresistance in glioma.