Glycolysis and the pentose phosphate pathway are differentially associated with the dichotomous regulation of glioblastoma cell migration versus proliferation

Abstract

Cell function and metabolic state are coupled independently of hypoxia, and glucose metabolic pathways are causatively involved in regulating "go or grow" cellular programs.

Fatty Acid Biosynthesis Inhibition Increases Reduction Potential in Neuronal Cells under Hypoxia

“…Surprisingly, hypoxia decreased ${\text{NADPH}}_2^{+}$/NADP + ratio. This is consistent with previous reports (Tribble and Jones, 1990; Gupte and Wolin, 2006; Kathagen-Buhmann et al, 2016) and may be associated with the depression of pentose-phosphate pathway (Gupte and Wolin, 2006; Kathagen-Buhmann et al, 2016). Alternatively, decreased ${\text{NADPH}}_2^{+}$ under hypoxia may be explained through significant increased FA synthesis that utilizes ${\text{NADPH}}_2^{+}$ as a cofactor.…”

“…In line with this mechanism, and consistent with previous studies when 1% O 2 was used to model hypoxia (Zhang et al, 2006), we observed a significant increase in the ${\text{NADH}}_2^{+}$/NAD + ratio and lactic acid accumulation in control hypoxic cells (Figures 2, 3). However, similar to previous reports (Tribble and Jones, 1990; Gupte and Wolin, 2006; Kathagen-Buhmann et al, 2016), hypoxia decreased the ${\text{NADPH}}_2^{+}$/NADP + ratio (Figure 2) which may be explained through the depression of the pentose-phosphate pathway(Gupte and Wolin, 2006; Kathagen-Buhmann et al, 2016). Alternatively, decreased ${\text{NADPH}}_2^{+}$ under hypoxia may be explained through significantly increased FA synthesis under hypoxia since FA synthesis utilizes ${\text{NADPH}}_2^{+}$ as a cofactor.…”

Molecular Mechanisms of Glioma Cell Motility

“…The "Go or Grow" is modulated by changes in the microenvironment like hypoxia or nutrient depletion, which prompts a tumor cell to "Go" in order to reach a more favorable environment and re-settle there, or to "Grow" if the environment provides enough oxygen and nutrients. The pentose phosphate pathway (PPP) is mainly used during proliferation, and glycolysis is used as the energy source during migration (5). Other parameters that influence the "Go or Grow" of glioma cells are the cell volume, cytoskeleton dynamics, and the ECM composition (27).…”

“…There are several cellular and environmental requirements that set the stage for a glioma cell to move. For example, migrating cells show changes in energy metabolism that are often induced by hypoxic conditions (5,6). Cytokines, chemokines, nutrition deprivation, and hypoxia lead to changes in the expression of transcription factors (TFs), and subsequently to altered protein expression (7).…”

Glycobiology Modifications in Intratumoral Hypoxia: The Breathless Side of Glycans Interaction

“…It was shown that G6PD (Glucose-6-phosphate dehydrogenase), a rate-limiting enzyme of PPP, is dynamically modified with an O-linked β-N-acetylglucosamine sugar in response to hypoxia in several lineages, such as hepatocarcinoma, melanoma, and breast cancer [41]. Inversely, it was found that expression of PPP enzymes, in particular G6PD and 6-phosphogluconate dehydrogenase, is downregulated by acute hypoxia and upregulated by oxygenation in glioblastomas cell lines, while glycolysis enzymes are downregulated [42]. …”