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

Danni Sun, Hongchun Liu, Xiaoyang Dai, Xingling Zheng, Juan Yan, Rongrui Wei, Xuhong Fu, Min Huang, Aijun Shen, Xun Huang, Jian Ding, Meiyu Geng

Cancer letters 2017 Oct 10

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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. Copyright © 2017 Elsevier B.V. All rights reserved.

Citation

Danni Sun, Hongchun Liu, Xiaoyang Dai, Xingling Zheng, Juan Yan, Rongrui Wei, Xuhong Fu, Min Huang, Aijun Shen, Xun Huang, Jian Ding, Meiyu Geng. Aspirin disrupts the mTOR-Raptor complex and potentiates the anti-cancer activities of sorafenib via mTORC1 inhibition. Cancer letters. 2017 Oct 10;406:105-115