Cell inactivation and cell cycle inhibition as induced by extreme hypoxia: the possible role of cell cycle arrest as a protection against hypoxia-induced lethal damage

Abstract

Cycling mammalian cells that are rendered extremely hypoxic (less than 4 ppm O2) tend to accumulate in a pre-DNA-synthesis stage. It is not clear whether or not this is the result of an active regulation by the cells. In the present study we have rendered cells, synchronized by mitotic selection, extremely hypoxic over a relatively long period of time (up to 48 h). We have recorded cell cycle progression during hypoxia as well as cell inactivation depending on where in the cell cycle the cells were located when the hypoxic treatment was started. Three main conclusions are drawn: 1 the cell cycle arrest in late-G1 is complete even during a long-lasting (24 h) hypoxic treatment: 2 while cells in early- and mid-S are completely arrested and quickly inactivated under hypoxic conditions, cells in late-S, G2 and mitosis are able to continue cell cycle progression and divide; 3 whether the cells are located in G2, mitosis or early-G1 at the onset of hypoxia, they were able to survive relatively long-lasting hypoxic treatment. The present results are in favour of the view that the pre-DNA-synthetic arrest induced by extreme hypoxia may function to rescue the cells from severely damaging effects that would appear if the cells were able to initiate DNA synthesis.