FTY720 抑制人神经胶质瘤细胞系中的 Nrf2/ARE 通路，并增强神经胶质瘤细胞对替莫唑胺的敏感性。

FTY720 inhibits the Nrf2/ARE pathway in human glioblastoma cell lines and sensitizes glioblastoma cells to temozolomide.

机构信息

Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, China.

出版信息

Pharmacol Rep. 2017 Dec;69(6):1186-1193. doi: 10.1016/j.pharep.2017.07.003. Epub 2017 Jul 4.

DOI:10.1016/j.pharep.2017.07.003

PMID:29128799

Abstract

BACKGROUND

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor regulating the expression of various cytoprotective genes. Constitutive Nrf2 activation in many cancers enhances cell survival and resistance to anti-cancer drugs. Our previous studies have shown that FTY720 induced autophagy-related apoptosis and necroptosis and inhibited invasion and migration in human glioblastoma cells. However, whether FTY720 regulated Nrf2 in glioblastoma cells remained unclear.

METHODS

Cell viability assay, western blot, migration and invasion assay, short hairpin RNA (shRNA) were used.

RESULTS

We found that FTY720 suppressed the protein and mRNA levels of Nrf2 in human U251MG and U87MG glioblastoma cells lines. In addition, the protein and mRNA levels of heme oxygenase-1 (HO-1) and NADPH:quinine oxidoreductase-1 (NQO-1), two representative target factors of Nrf2, also decreased upon FTY720 treatment. Knockdown of Nrf2 further promoted the anti-cancer effects of FTY720, while activation of Nrf2 exist the opposite effects. In addition, FTY720 significantly sensitized glioblastoma cells to temozolomide (TMZ). However, activation of Nrf2 essentially abolished the induced sensitivity by FTY720.

CONCLUSION

Our results indicated the potential application of FTY720 in treatment of glioblastoma and demonstrated that inhibition of Nrf2 can enhance the sensitivity of cancer cells to chemotherapeutic drugs.

摘要

背景

核因子红细胞 2 相关因子 2（Nrf2）是一种氧化还原敏感的转录因子，调节各种细胞保护基因的表达。许多癌症中 Nrf2 的组成性激活增强了细胞存活和对抗癌药物的耐药性。我们之前的研究表明，FTY720 诱导自噬相关的细胞凋亡和坏死，并抑制人胶质母细胞瘤细胞的侵袭和迁移。然而，FTY720 是否调节胶质母细胞瘤细胞中的 Nrf2 尚不清楚。

方法

细胞活力测定、western blot、迁移和侵袭测定、短发夹 RNA（shRNA）。

结果

我们发现 FTY720 抑制了人 U251MG 和 U87MG 胶质母细胞瘤细胞系中 Nrf2 的蛋白和 mRNA 水平。此外，FTY720 处理后，Nrf2 的两个代表性靶因子血红素加氧酶-1（HO-1）和 NADPH：醌氧化还原酶-1（NQO-1）的蛋白和 mRNA 水平也降低。Nrf2 的敲低进一步促进了 FTY720 的抗癌作用，而 Nrf2 的激活则产生相反的效果。此外，FTY720 显著增加了胶质母细胞瘤细胞对替莫唑胺（TMZ）的敏感性。然而，Nrf2 的激活基本上消除了 FTY720 诱导的敏感性。