Smurf1 silencing restores PTEN expression that ameliorates progression of human glioblastoma and sensitizes tumor cells to mTORC1/C2 inhibitor Torin1

被引：9

作者：

Xia, Qin ^{[1
]}

Li, Wenxuan ^{[1
]}

Ali, Sakhawat ^{[1
]}

Xu, Mengchuan ^{[1
]}

Li, Yang ^{[1
]}

Li, Shengzhen ^{[1
]}

Meng, Xinyi ^{[1
]}

Liu, Liqun ^{[1
]}

Dong, Lei ^{[1
]}

机构：

[1] Beijing Inst Technol, Sch Life Sci, Beijing 100081, Peoples R China

来源：

ISCIENCE | 2021年 / 24卷 / 12期

基金：

美国国家科学基金会; 中国国家自然科学基金;

关键词：

GLIOMA-CELLS; EGFR; MUTATIONS; PROTEIN; GROWTH; GENES; PROLIFERATION; COMBINATION; SUPPRESSION; PATHWAYS;

D O I：

10.1016/j.isci.2021.103528

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Amplification of ubiquitin E3 ligase Smurf1 promotes degradation of PTEN leading to hyperactivation of the Akt/mTORC1 pathway. However, inhibitors of this pathway have not hitherto yielded promising results in clinical studies because of strong drug resistance. Here, we investigated Smurf1 expression in various glioblastoma (GB) cell lines and patient tissues. The therapeutic efficacy of Smurf1 silencing and Torin1 treatment was assessed in GB cells and orthotopic mouse model. We found Smurf1 loss elevates PTEN levels that interrupt the epidermal growth factor receptor pathway activity. Cotreatment with Smurf1 silencing and mTORC1/C2 inhibitor Torin1 remarkably decreased phosphorylation of Akt, and mTORC1 downstream targets 4EBP1 and S6K resulting in synergistic inhibitory effects. Smurf1 knockdown in orthotopic GB mouse model impaired tumor growth and enhanced cytotoxicity of Torin1. Together, these finengs suggest a rational combination of Smurf1 inhibition and Torin1 as a promising new avenue to circumvent PI3K/Akt pathway-driven tumor progression and drug resistance.

引用

页数：18

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