Translational repression during chronic hypoxia is dependent on glucose levels

Abstract

Translation is often repressed in cell lines that are exposed to hypoxic conditions (0.5% -1.5% O 2 ) but this repression requires prolonged exposure (> 16 h). We report here that prolonged exposure to hypoxia results in the depletion of glucose from the media and that the loss of glucose correlates with the shut down in translation. Furthermore, we show that the addition of glucose or reoxygenation restores translation in hypoxic PC3 cells. This indicates that both glucose depletion and hypoxia are required for translational repression. We also show that eIF2a phosphorylation is reversed by glucose addition. Moreover, we present data that strongly indicate that eIF2a phosphorylation as well as the translational inhibition that occurs when cells are grown under conditions of glucose depletion and hypoxia is pancreatic eIF2a kinase (PERK) independent. We believe this is the first report to show that glucose depletion is required for translational repression under hypoxic conditions and that this explains why prolonged exposure to hypoxia is required for this inhibition. Since the physiological conditions that lead to tumor hypoxia would also likely lead to reduced glucose levels, understanding the interplay of glucose and hypoxia in regulating tumor metabolism will provide important information on the growth and development of solid tumors.

Functional Interaction between Responses to Lactic Acidosis and Hypoxia Regulates Genomic Transcriptional Outputs

“…In contrast, the simultaneous presence of both hypoxia and lactic acidosis dramatically induced S6K1 dephosphorylation and eIF2α phosphorylation, which may account for the inhibition of HIF-1α protein during stress. Interestingly, glucose deprivation was shown to inhibit the translation of HIF-1α under hypoxia (39). Given the high similarity of the gene expression response between lactic acidosis and glucose deprivation (13), it is likely that both lactic acidosis and glucose deprivation share similar mechanisms on the translation inhibition of HIF-1α.…”

Ribosome profiling reveals translational regulation of mammalian cells in response to hypoxic stress

“…However, there are certain differences between cellular responses to short-term and long-term hypoxic stress. Short-term hypoxia affects translational initiation via PERK-mediated eIF2α-phosphorylation, whereas prolonged hypoxia-induced translational change is regulated via down-regulation of mTOR activity mediated by REDD1 and AMPK, a process of PERK-independent eIF2α phosphorylation [ 9 ] and translational elongation [ 7 ]. Upon exposure to hypoxia, mTOR was inhibited via the tuberous sclerosis complex 1 and 2 (TSC1/2) in response to a shortage of energy production and REDD1, which is a transcriptional target of HIF-1α [ 10 ].…”

Hypoxia-inducible Factor-1α (HIF-1α) Promotes Cap-dependent Translation of Selective mRNAs through Up-regulating Initiation Factor eIF4E1 in Breast Cancer Cells under Hypoxia Conditions

“…Moderate hypoxia (1.5% O 2 ) in combination with serum deprivation effectively inhibits mTOR activity and causes hypophosphorylation of the mTOR substrates 4E-BP1and S6K in normal cells (16). Translational repression in cancer cells under chronic hypoxia and glucose depletion is independent of the eIF2␣ kinase PKR-like endoplasmic reticulum kinase (4,17).…”