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Inhibition of mTOR pathway sensitizes acute myeloid leukemia cells to aurora inhibitors by suppression of glycolytic metabolism
- Source :
- Molecular cancer research : MCR. 11(11)
- Publication Year :
- 2013
-
Abstract
- Aurora kinases are overexpressed in large numbers of tumors and considered as potential therapeutic targets. In this study, we found that the Aurora kinases inhibitors MK-0457 (MK) and ZM447439 (ZM) induced polyploidization in acute myeloid leukemia (AML) cell lines. The level of glycolytic metabolism was significantly increased in the polyploidy cells, which were sensitive to glycolysis inhibitor 2-deoxy-D-glucose (2DG), suggesting that polyploidy cells might be eliminated by metabolism deprivation. Indeed, inhibition of mTOR pathway by mTOR inhibitors (rapamycin and PP242) or 2DG promoted not only apoptosis but also autophagy in the polyploidy cells induced by Aurora inhibitors. Mechanically, PP242 or2DGdecreased the level of glucose uptake and lactate production in polyploidy cells as well as the expression of p62/SQSTM1. Moreover, knockdown of p62/SQSTM1 sensitized cells to the Aurora inhibitor whereas overexpression of p62/SQSTM1 reduced drug efficacy. Thus, our results revealed that inhibition of mTOR pathway decreased the glycolytic metabolism of the polyploidy cells, and increased the efficacy of Aurora kinases inhibitors, providing a novel approach of combination treatment in AML. Mol Cancer Res; 11(11); 1326–36. ©2013 AACR.
- Subjects :
- Cancer Research
Myeloid
Indoles
Aurora inhibitor
Antineoplastic Agents
HL-60 Cells
Biology
Deoxyglucose
Piperazines
Polyploidy
chemistry.chemical_compound
Aurora Kinases
Cell Line, Tumor
Sequestosome-1 Protein
medicine
Humans
Lactic Acid
Molecular Biology
PI3K/AKT/mTOR pathway
Adaptor Proteins, Signal Transducing
Sirolimus
Kinase
TOR Serine-Threonine Kinases
Autophagy
Myeloid leukemia
U937 Cells
medicine.disease
ZM447439
Cell biology
Gene Expression Regulation, Neoplastic
Leukemia
Leukemia, Myeloid, Acute
medicine.anatomical_structure
Glucose
Oncology
chemistry
Purines
Benzamides
Cancer research
Quinazolines
Glycolysis
Signal Transduction
Subjects
Details
- ISSN :
- 15573125
- Volume :
- 11
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- Molecular cancer research : MCR
- Accession number :
- edsair.doi.dedup.....dcbc4bb633100507a106e0d4e722aae8