Cellular Prion Protein (PrPc) and Hypoxia: True to Each Other in Good Times and in Bad, in Sickness, and in Health

Abstract

The cellular prion protein (PrPc) and hypoxia appear to be tightly intertwined. Beneficial effects of PrPc on neuronal survival under hypoxic conditions such as focal cerebral ischemia are strongly supported. Conversely, increasing evidence indicates detrimental effects of increased PrPc expression on cancer progression, another condition accompanied by low oxygen tensions. A switch between anaerobic and aerobic metabolism characterizes both conditions. A cellular process that might unite both is glycolysis. Putative role of PrPc in stimulation of glycolysis in times of need is indeed thought provoking. A significance of astrocytic PrPc expression for neuronal survival under hypoxic conditions and possible association of PrPc with the astrocyte-neuron lactate shuttle is considered. We posit PrPc-induced lactate production via transactivation of lactate dehydrogenase A by hypoxia inducible factor 1α as an important factor for survival of both neurons and tumor cells in hypoxic microenvironment. Concomitantly, we discuss a cross-talk between Wnt/β-catenin and PI3K/Akt signaling pathways in executing PrPc-induced activation of glycolysis. Finally, we would like to emphasize that we see a great potential in joining expertise from both fields, neuroscience and cancer research in revealing the mechanisms underlying hypoxia-related pathologies. PrPc may prove focal point for future research.

Altered mRNA and Protein Expression of Monocarboxylate Transporter MCT1 in the Cerebral Cortex and Cerebellum of Prion Protein Knockout Mice

“…In the last few years, various reports have indicated the involvement of PrP c in the maintenance of glucose homeostasis [ 1 , 2 , 3 , 4 , 5 ]. Besides this, an effect of PrP c on glycolysis was suggested in several earlier studies [ 6 , 7 , 8 ]. A recent metabolomic analysis demonstrated reduced glycolysis and glucose utilization in the hippocampus and the cortex of prion-diseased mice [ 2 ].…”

The Cellular Prion Protein and the Hallmarks of Cancer

“…In line with this, Alfaidy et al suggested that PrP C is involved in placental angiogenesis by controlling the proliferation, migration and tube-like organisation of trophoblastic cells [ 72 ]. This study further showed an upregulation of PrP C in response to hypoxia [ 72 ], which is now quite well established under various paradigms (reviewed in [ 73 ]). The HIF1α-dependent control on PrP C expression actually extends to the stabilisation of the protein through the sequestration of the E3 ligase GP78 by hypoxia-induced HSPA1L ( Figure 3 ), as shown by Lee et al in colorectal cancer cells [ 56 ].…”

Harnessing the Physiological Functions of Cellular Prion Protein in the Kidneys: Applications for Treating Renal Diseases

“…Although many signaling pathways are reportedly activated or inhibited by PrP C , the existence of extensive crosstalk networks between the pathways, coupled with the differential expression of suspected binding partners of PrP C in different tissues/cell types, point towards the probability that there will be a difference in the degree of involvement for the primary and secondary downstream effectors of PrP C [ 7 ]. For example, in the PrP C -induced activation of glycolysis in cerebral ischemia, crosstalk between the Wnt/β-catenin and PI3K/Akt signaling pathways is the executor of glycolysis activation, but PrP C interaction with the PI3K/Akt pathway is better documented [ 7 , 203 ]. Mapping the full regulatory network for PrP C in a physiological context could help us identify which cellular pathways are better targeted with PrP C -based interventions for specific renal diseases.…”