Inhibition of mTOR Pathway Sensitizes Acute Myeloid Leukemia Cells to Aurora Inhibitors by Suppression of Glycolytic Metabolism

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. Ó2013 AACR.

A novel compound against oncogenic Aurora kinase A overcomes imatinib resistance in chronic myeloid leukemia cells

“…In addition, AKI603 treatment initially resulted in G2/M cell cycle arrest and significant degree of aneuploidy (Fig. 2), a typical phenotype of Aurora suppression (24). These data were consistent with our finding in AML and solid tumor cells that inhibition of Aurora induced cell cycle arrest, promoted polyploidy formation and inhibited cell proliferation (24-26).…”

“…Disruption of Aurora kinase activity induces abnormal spindle pole organization, centrosome separation and chromosome congression (23). Ultimately, cells treated with Aurora kinase inhibitor undergo cell growth inhibition through the development of deleterious aneuploidy (24,25). In this report, we found that AKI603 inhibited Aur-A kinase and presented anti-leukemia effects in KBM5 cells, as well as KBM5-T315I cells, suggesting a possible novel and potent target in treating imatinib-resistant CML.…”

Alisertib (MLN8237), a selective Aurora-A kinase inhibitor, induces apoptosis in human tongue squamous cell carcinoma cell both in vitro and in vivo

“…Inhibition of Aurora-A kinases could inhibit proliferation, viability, migration, and invasion of gastric cancer cells [6]. Recent studies showed that kinase inhibition of Aurora-A triggered autophagy in breast cancer and leukemia cells [7,8].…”

Targeting the mitochondria in acute myeloid leukemia

“…These polyploid cells showed increased consumption of glucose and increased production of lactase. Cell viability decreased with increasing concentration of 2-DG [23]. Expression of mutant Cbl (Casitas B-lineage lymphoma) proto-oncogene (CBL) in FLT3-expressing Ba/F3 cells increased ROS production and enhanced glucose consumption.…”