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

Sanja Ramljak, Holger Herlyn, Inga Zerr

The cellular prion protein (PrP(c)) and hypoxia appear to be tightly intertwined. Beneficial effects of PrP(c) on neuronal survival under hypoxic conditions such as focal cerebral ischemia are strongly supported. Conversely, increasing evidence indicates detrimental effects of increased PrP(c) 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 PrP(c) in stimulation of glycolysis in times of need is indeed thought provoking. A significance of astrocytic PrP(c) expression for neuronal survival under hypoxic conditions and possible association of PrP(c) with the astrocyte-neuron lactate shuttle is considered. We posit PrP(c)-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 PrP(c)-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. PrP(c) may prove focal point for future research.