Differential expression of adenylate kinase 4 in the context of disparate stress response strategies of HEK293 and HepG2 cells

Adenylate kinase isozyme 4 (AK4) belongs to a family of nucleotide monophosphate kinases involved in energy metabolism. Recently, AK4 was reported to play a role in protection from stress: In HEK293 cells, hypoxia increases AK4 expression but does not affect proliferation or viability, while RNA interference (RNAi) directed against AK4 inhibits proliferation and promotes death. By contrast, we show here that HepG2 cells showed much higher AK4 levels, which decreased under hypoxia along with markedly reduced cell proliferation and increased cell death. Nevertheless, RNAi directed against AK4 inhibited cell proliferation and caused death in both cell types, although cell cycle parameters were affected only in HepG2 cells. Hence reductions of AK4 levels were always associated with cell death. These results extend the notion of a stress-protective function of AK4 to a novel physiological context and show that AK4-mediated stress protection is not limited to one particular death scenario. Our data also allow the hypothesis that the different basal AK4 levels reflect different basal stress levels, causing alternative responses to additional stress.

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► HepG2 cells show a much higher basal AK4 expression than HEK293 cells.
► HEK293 cells increase, but HepG2 cells decrease, AK4 levels under hypoxia.
► HEK293 cells survive, but HepG2 cells die, under hypoxia.
► Under normoxia, RNAi directed against AK4 caused death in both cell types.
► Thus cell death was always observed when AK4 levels were decreased.