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Effect of Low Glutamine/Glucose on Hypoxia-Induced Elevation of Hypoxia-Inducible Factor-1 in Human Pancreatic Cancer MiaPaCa-2 and Human Prostatic Cancer DU-145 Cells

Authors' Affiliation: Department of Surgery and Pharmacology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

Requests for reprints: Yong J. Lee, Department of Surgery, University of Pittsburgh, Hillman Cancer Center, 5117 Center Avenue, Room G.5a, Pittsburgh, PA 15213. Phone: 412-623-3268; Fax: 412-623-1010; E-mail: leeyj{at}msx.upmc.edu.

Purpose and Experimental Design: Tumor microenvironment is characterized by regions of fluctuating and chronic hypoxia, low extracellular pH, and nutrient depletion. Although it is well known that hypoxia stimulates the accumulation of hypoxia-inducible factor-1 (HIF-1), the role of low extracellular pH and nutrient depletion on hypoxia up-regulation of HIF-1 is not well known. In this study, human pancreatic cancer MiaPaCa-2 and human prostatic cancer DU-145 cells were exposed to hypoxia in the presence or absence of glucose, glutamine, and/or pyruvate.

Results: We observed that low glucose and low glutamine, but not low pyruvate, effectively suppressed the elevation of HIF-1 level during hypoxia (0.1-1% oxygen). Deprivation of glutamine or glucose inhibited the accumulation of HIF-1 in the presence of MG-132, a protease inhibitor, regardless of oxygen tensions. Data from reverse transcription-PCR analysis revealed that the levels of HIF-1 mRNA were not significantly changed at different concentrations of glutamine or glucose under hypoxia. The amount of HIF-1 suppression was proportional to protein synthesis inhibition.

Conclusions: Our data suggest that glutamine or glucose deprivation inhibits the accumulation of HIF-1 under hypoxic conditions by disrupting translational processes rather than transcriptional or proteasomal degradation processes.

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