Glycogen Synthesis is Induced in Hypoxia by the Hypoxia-Inducible Factor and Promotes Cancer Cell Survival

The hypoxia-inducible factor 1 (HIF-1), in addition to genetic and epigenetic changes, is largely responsible for alterations in cell metabolism in hypoxic tumor cells. This transcription factor not only favors cell proliferation through the metabolic shift from oxidative phosphorylation to glycolysis and lactic acid production but also stimulates nutrient supply by mediating adaptive survival mechanisms. In this study we showed that glycogen synthesis is enhanced in non-cancer and cancer cells when exposed to hypoxia, resulting in a large increase in glycogen stores. Furthermore, we demonstrated that the mRNA and protein levels of the first enzyme of glycogenesis, phosphoglucomutase1 (PGM1), were increased in hypoxia. We showed that induction of glycogen storage as well as PGM1 expression were dependent on HIF-1 and HIF-2. We established that hypoxia-induced glycogen stores are rapidly mobilized in cells that are starved of glucose. Glycogenolysis allows these “hypoxia-preconditioned” cells to confront and survive glucose deprivation. In contrast normoxic control cells exhibit a high rate of cell death following glucose removal. These findings point to the important role of hypoxia and HIF in inducing mechanisms of rapid adaptation and survival in response to a decrease in oxygen tension. We propose that a decrease in pO2 acts as an “alarm” that prepares the cells to face subsequent nutrient depletion and to survive

Measurement of geophysical parameters on clay samples at the solid–fluid transition

International audienceFluidisation occurring in clay-rich landslides poses serious threats to populations and infrastructures and has been the subject of numerous studies to apprehend its rheological origin. In parallel, noninvasive geophysical techniques on landslides have known considerable development as a means to approach in-situ geotechnical parameters. This study investigates the influence of fluidisation on two geophysical parameters: the shear wave velocity, Vs, and the electrical resistivity, ρ. Both parameters are widely used in landslide monitoring as they are sensitive, respectively, to soil stiffness and water content, two key parameters for material fluidisation. Laboratory tests were carried out on soil samples collected in five flow-like landslides occurring in very different geological conditions. A plate–plate rheometer was used to provoke fluidisation, and Vs was measured during oscillatory tests. The rheometer was redesigned for resistivity measurements, incorporating circular electrodes in polyvinyl chloride plates. Results show that (i) all soils exhibit a dramatic drop in Vs at the fluidisation, and (ii) the resistivity does not significantly vary at the solid–fluid transition. These last results are analysed in terms of clay particles arrangement using the electrical laws of Archie and Waxman–Smits, and the impact on landslide geophysical monitoring is discussed

Hypoxia-Induced Autophagy Is Mediated through Hypoxia-Inducible Factor Induction of BNIP3 and BNIP3L via Their BH3 Domains▿ †

While hypoxia-inducible factor (HIF) is a major actor in the cell survival response to hypoxia, HIF also is associated with cell death. Several studies implicate the HIF-induced putative BH3-only proapoptotic genes bnip3 and bnip3l in hypoxia-mediated cell death. We, like others, do not support this assertion. Here, we clearly demonstrate that the hypoxic microenvironment contributes to survival rather than cell death by inducing autophagy. The ablation of Beclin1, a major actor of autophagy, enhances cell death under hypoxic conditions. In addition, the ablation of BNIP3 and/or BNIP3L triggers cell death, and BNIP3 and BNIP3L are crucial for hypoxia-induced autophagy. First, while the small interfering RNA-mediated ablation of either BNIP3 or BNIP3L has little effect on autophagy, the combined silencing of these two HIF targets suppresses hypoxia-mediated autophagy. Second, the ectopic expression of both BNIP3 and BNIP3L in normoxia activates autophagy. Third, 20-mer BH3 peptides of BNIP3 or BNIP3L are sufficient in initiating autophagy in normoxia. Herein, we propose a model in which the atypical BH3 domains of hypoxia-induced BNIP3/BNIP3L have been designed to induce autophagy by disrupting the Bcl-2-Beclin1 complex without inducing cell death. Hypoxia-induced autophagy via BNIP3 and BNIP3L is clearly a survival mechanism that promotes tumor progression

The Mitochondrial Apoptosis-induced Channel (MAC) Corresponds to a Late Apoptotic Event

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