Effect of low glutamine/glucose on hypoxia-induced elevation of hypoxia-inducible factor-1α in human pancreatic cancer MiaPaCa-2 and human prostatic cancer DU-145 cells

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 alpha (HIF-1 alpha), the role of low extracellular pH and nutrient depletion on hypoxia up-regulation of HIF-1 alpha 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 alpha level during hypoxia (0.1-1% oxygen). Deprivation of glutamine or glucose inhibited the accumulation of HIF-1 alpha 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 alpha mRNA were not significantly changed at different concentrations of glutamine or glucose under hypoxia. The amount of HIF-1 alpha suppression was proportional to protein synthesis inhibition. Conclusions: Our data suggest that glutamine or glucose deprivation inhibits the accumulation of HIF-1 alpha under hypoxic conditions by disrupting translational processes rather than transcriptional or proteasomal degradation processes.