Aspirin disrupts the mTOR-Raptor complex and potentiates the anti-cancer activities of sorafenib via mTORC1 inhibition

被引：32

作者：

Sun, Danni ^{[1
]}

Liu, Hongchun ^{[1
]}

Dai, Xiaoyang ^{[1
]}

Zheng, Xingling ^{[1
]}

Yan, Juan ^{[1
]}

Wei, Rongrui ^{[1
]}

Fu, Xuhong ^{[1
]}

Huang, Min ^{[1
]}

Shen, Aijun ^{[1
]}

Huang, Xun ^{[1
]}

Ding, Jian ^{[1
]}

Geng, Meiyu ^{[1
]}

机构：

[1] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China

来源：

CANCER LETTERS | 2017年 / 406卷

关键词：

Aspirin; mTORC1; AMPK; Sorafenib; Proliferation; ACTIVATED PROTEIN-KINASE; HISTONE DEACETYLASE INHIBITORS; BRAF-MUTATION STATUS; COLORECTAL-CANCER; CELL-GROWTH; HEPATOCELLULAR-CARCINOMA; MAMMALIAN TARGET; RAPAMYCIN; COMBINATION; PATHWAY;

D O I：

10.1016/j.canlet.2017.06.029

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Aspirin is associated with a reduced risk of cancer and delayed progression of malignant disease. Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)-mTOR signaling is believed to partially contribute to these anticancer effects, although the mechanism is unclear. In this study, we revealed the mechanism underlying the effects of aspirin on AMPK-mTOR signaling, and described a mechanism-based rationale for the use of aspirin in cancer therapy. We found that aspirin inhibited mTORC1 signaling through AMPK-dependent and-independent manners. Aspirin inhibited the AMPK-TSC pathway, thus resulting in the suppression of mTORC1 activity. In parallel, it directly disrupted the mTOR-raptor interaction. Additionally, the combination of aspirin and sorafenib showed synergetic effects via inhibiting mTORC1 signaling and the PI3K/AKT, MAPK/ERK pathways. Aspirin and sorafenib showed synergetic anticancer efficacy in the SMMC-7721 model. Our study provides mechanistic insights and a mechanism-based rationale for the roles of aspirin in cancer treatment. (C) 2017 Elsevier B.V. All rights reserved.

引用

页码：105 / 115

页数：11

共 47 条

[1] Aspirin Use for the Primary Prevention of Cardiovascular Disease and Colorectal Cancer: US Preventive Services Task Force Recommendation Statement [J].