Animal cells need growth factors and nutrients for their survival. When depleted of growth factors, cells undergo apoptosis, whereas nutrient starvation leads to a process known as macroautophagy, during which basal ATP production is maintained by catabolizing intracellular substrates, to allow short-term cell survival. Reporting their findings in Cell, Craig Thompson and colleagues now show that, even in the presence of excess nutrients, apoptosis-deficient cells that are deprived of growth factors undergo macroautophagy.

Using cells from interleukin (IL)-3-dependent Bax−/− Bak−/− mice, which are apoptosis deficient, Thompson and co-workers noticed that cells shrank in size in response to IL-3 withdrawal and showed a prolonged survival until, after ∼12 weeks, they started to die. Cells also showed metabolic changes, including reduced glycolysis and a drop in ATP levels, as well as reduced cell-surface expression of the nutrient transporter GLUT1 and the formation of autophagosomes, which are characteristic of macroautophagy.

To analyse whether macroautophagy was responsible for the survival of growth-factor-deprived cells, Thompson and colleagues inhibited autophagy by RNA interference — after which cells indeed started to die. When cells that had been deprived of IL-3 for several weeks were treated with macroautophagy inhibitors, cell death could be reversed by supplying cells with an alternative metabolic substrate to maintain oxidative phosphorylation and, therefore, ATP production. This shows that the continued degradation of metabolic substrates is important to maintain cell viability, even at late time points after growth-factor withdrawal. Importantly, macroautophagy was induced by growth-factor withdrawal, and not by a lack of nutrients, as the IL-3-depleted cells were kept in rich culture medium.

Next, the Thompson group showed that when IL-3-deprived cells were resupplied with IL-3, the rate of glycolysis increased within hours, which reflects their ability to take up and metabolize glucose again. The recovery time for cells to start growing and proliferating took longer, and depended on the length of IL-3 deprivation. Virtually all cells that were deprived of IL-3 for 2 or 6 weeks recovered, so growth-factor-mediated signal transduction is ultimately required for cell survival.

The authors concluded that, in addition to regulating apoptosis, growth factors seem to promote cell survival by enabling cells to take up sufficient nutrients for limited self-maintenance. This dual role makes them essential survival factors.