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

• Published in: Cancer letters 2017-10, Vol.406, p.105-115
• Main Authors: Sun, Danni, Liu, Hongchun, Dai, Xiaoyang, Zheng, Xingling, Yan, Juan, Wei, Rongrui, Fu, Xuhong, Huang, Min, Shen, Aijun, Huang, Xun, Ding, Jian, Geng, Meiyu
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Adaptor Proteins, Signal Transducing - antagonists & inhibitors; Adaptor Proteins, Signal Transducing - metabolism; AKT protein; AMP; AMP-Activated Protein Kinases - physiology; AMPK; Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Aspirin; Aspirin - pharmacology; Cancer; Cancer therapies; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell growth; Cell Proliferation - drug effects; Cells, Cultured; Drug therapy; Drug Therapy, Combination; Embryo, Mammalian - cytology; Embryo, Mammalian - drug effects; Embryo, Mammalian - metabolism; Extracellular signal-regulated kinase; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - metabolism; Gene Expression Regulation, Neoplastic - drug effects; Health risks; Humans; Inhibitor drugs; Kinases; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; MAP kinase; Mechanistic Target of Rapamycin Complex 1; Metabolic pathways; Mice; Mice, Knockout; mTORC1; Multiprotein Complexes - antagonists & inhibitors; Multiprotein Complexes - metabolism; Niacinamide - analogs & derivatives; Niacinamide - pharmacology; Phenylurea Compounds - pharmacology; Proliferation; Protein kinase; Regulatory-Associated Protein of mTOR; Signal transduction; Sorafenib; Targeted cancer therapy; TOR protein; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - metabolism; Tumor Suppressor Proteins - metabolism; Xenograft Model Antitumor Assays
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2017.06.029

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. •Aspirin inhibits mTORC1 signaling in an AMPK-independent manner.•Aspirin disrupts the mTOR-raptor interaction.•mTORC1 inhibition contributed to the synergistic effect of aspirin combining with sorafenib.