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Aspirin disrupts the mTOR-Raptor complex and potentiates the anti-cancer activities of sorafenib via mTORC1 inhibition.
- Source :
-
Cancer Letters . Oct2017, Vol. 406, p105-115. 11p. - Publication Year :
- 2017
-
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. [ABSTRACT FROM AUTHOR]
- Subjects :
- *ASPIRIN
*MTOR protein
*SORAFENIB
*CANCER risk factors
*ADENOSINE monophosphate
*THERAPEUTICS
*PROTEIN metabolism
*ANIMALS
*ANTINEOPLASTIC agents
*APOPTOSIS
*CARRIER proteins
*CELL culture
*CELL physiology
*COMBINATION drug therapy
*FIBROBLASTS
*GENES
*HEPATOCELLULAR carcinoma
*LIVER tumors
*MICE
*NONSTEROIDAL anti-inflammatory agents
*PHOSPHOTRANSFERASES
*PROTEINS
*UREA
*VITAMIN B complex
*EMBRYOS
*CHEMICAL inhibitors
*PHARMACODYNAMICS
Subjects
Details
- Language :
- English
- ISSN :
- 03043835
- Volume :
- 406
- Database :
- Academic Search Index
- Journal :
- Cancer Letters
- Publication Type :
- Academic Journal
- Accession number :
- 124999057
- Full Text :
- https://doi.org/10.1016/j.canlet.2017.06.029