Legend
Evading growth suppressors
Sustaining proliferative signaling
Enabling replicative immortality
Genome instability and mutation
Hypoxia suppresses conversion from proliferative arrest to cellular senescence.
Unlike reversible quiescence, cellular senescence is characterized by a large flat cell morphology, beta-gal staining and irreversible loss of regenerative (i.e., replicative) potential. Conversion from proliferative arrest to irreversible senescence, a process named geroconversion, is driven in part by growth-promoting pathways such as mammalian target of rapamycin (mTOR). During cell cycle arrest, mTOR converts reversible arrest into senescence. Inhibitors of mTOR can suppress geroconversion, maintaining quiescence instead. It was shown that hypoxia inhibits mTOR. Therefore, we suggest that hypoxia may suppress geroconversion. Here we tested this hypothesis. In HT-p21-9 cells, expression of inducible p21 caused cell cycle arrest without inhibiting mTOR, leading to senescence. Hypoxia did not prevent p21 induction and proliferative arrest, but instead inhibited the mTOR pathway and geroconversion. Exposure to hypoxia during p21 induction prevented senescent morphology and loss of regenerative potential, thus maintaining reversible quiescence so cells could restart proliferation after switching p21 off. Suppression of geroconversion was p53- and HIF-1-independent, as hypoxia also suppressed geroconversion in cells lacking functional p53 and HIF-1alpha. Also, in normal fibroblasts and retinal cells, hypoxia inhibited the mTOR pathway and suppressed senescence caused by etoposide without affecting DNA damage response, p53/p21 induction and cell cycle arrest. Also hypoxia suppressed geroconversion in cells treated with nutlin-3a, a nongenotoxic inducer of p53, in cell lines susceptible to nutlin-3a-induced senescence (MEL-10, A172, and NKE). Thus, in normal and cancer cell lines, hypoxia suppresses geroconversion caused by diverse stimuli. Physiological and clinical implications of the present findings are discussed.