HIF-1α and GLUT1 Gene Expression is Associated with Chemoresistance of Acute Myeloid Leukemia

Kui Song,Xiao-Ling Song,Xiao-Jun Xu,Li Xuan,Qi-Fa Liu,Gui-Nian Huang,Min Li

doi:10.7314/apjcp.2014.15.4.1823

Abstract

Much evidence suggests that increased glucose metabolism in tumor cells might contribute to the development of acquired chemoresistance. However, the molecular mechanisms are not fully clear. Therefore, we investigated a possible correlation of mRNA expression of HIF-1α and GLUT1 with chemoresistance in acute myeloid leukemia (AML). Bone marrow samples were obtained from newly diagnosed and relapsed AML (M3 exclusion) cases. RNA interference with short hairpin RNA (shRNA) was used to stably silence GLUT1 or HIF-1α gene expression in an AML cell line and HIF-1α and GLUT1 mRNA expression was measured by real-time quantitative polymerase chain reaction assay (qPCR). High levels of HIF-1α and GLUT1 were associated with poor responsiveness to chemotherapy in AML. Down-regulation of the expression of GLUT1 by RNA interference obviously sensitized drug-resistant HL-60/ADR cells to adriamycin (ADR) in vitro, comparable with RNA interference for the HIF-1α gene. Our data revealed that over-expression of HIF-1α and GLUT1 might play a role in the chemoresistance of AML. GLUT1 might be a potential target to reverse such drug resistance.

Highlights

The majority of tumors are known to have an altered metabolism compared their origin tissue, with high rates of glucose uptake and glycolysis, which meets the energy need for unlimited proliferation of tumor cells (Bayley et al, 2012; Wynn et al, 2012)
Hypoxia inducible factor 1a (HIF-1a) is a transcriptional factor that up-regulates the expression of specific isoforms of glucose transporter (GLUT), hexokinase (HK), phosphofructokinase (PFK)-1, PFK-2, aldolase (ALD), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), phosphoglycerate kinase (PGK), phosphoglycerate mutase (PGAM), enolase (ENO), pyruvate kinase (PYK), and lactate dehydrogenase (LDH) (Robey et al, 2005)
A GLUT1 mRNA expression was suppressed in HL-60/ADR cells stably transfected by pLVX-short hairpin RNA (shRNA)- GLUT1

Summary

Introduction

The majority of tumors are known to have an altered metabolism compared their origin tissue, with high rates of glucose uptake and glycolysis, which meets the energy need for unlimited proliferation of tumor cells (Bayley et al, 2012; Wynn et al, 2012). The higher expression of GLUT1 were demonstrated in ALL cells (Manel et al, 2005), which produce the high levels of lactate and are sensitive to the glycolysis inhibitor 2-deoxy-Dglucose (2DG) (Hulleman et al, 2009). This provides an empirical evidence that acute leukemic cells might have a similar metabolic profile with solid tumors. Several mechanisms for the enhanced glycolysis in tumor cells have been proposed Among these mechanisms, HIF-1α and GLUT1 play the important roles in genetic regulation of glycolysis and altered glucose metabolism in tumor cells. We investigated a possible correlation of the expressions of HIF-1α and GLUT1 with chemoresistance in AML cells

Materials and Methods

Results

Discussion