Aspirin disrupts the mTOR-Raptor complex and potentiates the anti-cancer activities of sorafenib via mTORC1 inhibition
D Sun, H Liu, X Dai, X Zheng, J Yan, R Wei, X Fu… - Cancer letters, 2017 - Elsevier
Cancer letters, 2017•Elsevier
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 …
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 …
Abstract
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.
Elsevier
