Autophagy is a cellular catabolic degradation response to starvation or stress whereby cellular proteins, organelles and cytoplasm are engulfed, digested and recycled to sustain cellular metabolism1,2
. Constitutive, basal autophagy also has an important homeostatic function, maintaining protein and organelle quality control, acting in parallel with the ubiquitin proteasome degradation pathway to prevent the accumulation of polyubiquitinated and aggregated proteins3–8
. Autophagy is also a pathway that is used for the elimination of pathogens9
and for the engulfment of apoptotic cells10
. However, the effect of these events on cancer is not known. Although most evidence supports a role for autophagy in sustaining cell survival, paradoxically, cell death resulting from progressive cellular consumption has been attributed to unrestrained autophagy11–13
Complicating this situation further, cytotoxic events often induce autophagy, but whether this is a death mechanism or a futile effort at cellular preservation is often unclear2
. Another enigma has been the role of autophagy in tumour suppression; allelic loss of the essential autophagy gene beclin1 (BECN1
, also known as ATG6
) is found with high frequency in human breast, ovarian and prostate cancers14,15
, and autophagy-defective Becnl-heterozygous16,17
and autophagy-related 4C (Atg4C)-deficient18
mice are prone to tumours. Paradoxically, most evidence supports a role for autophagy in maintaining tumour cell survival in response to metabolic stress in vitro
, and in hypoxic tumour regions in vivo19–23
. Resolution of these paradoxes surrounding autophagy function has proved challenging.
The mechanisms that regulate the mutually opposed survival-supporting and death-promoting roles for autophagy are still far from resolution. The most plausible explanation is that catabolism through autophagy is predominantly survival-supporting, but that an imbalance in cell metabolism, where autophagic cellular consumption exceeds the cellular capacity for synthesis, promotes cell death. Although experimental evidence to support this is currently lacking, insight into the role of autophagy in tumour suppression is beginning to evolve.
How loss of the pro-survival function of autophagy promotes tumorigenesis is partly explained by the stimulation of necrotic cell death and an inflammatory response in tumours with defects in autophagy and apoptosis19
. Preventing survival under starvation through autophagy, and diverting apoptosis-defective tumour cells to a necrotic cell fate, generates chronically necrotic tumours. This can corrupt a normal wound-healing response to support tumour growth, representing a possible means by which autophagy defects provide a non-cell-autonomous mechanism for stimulating tumorigenesis24–26
. In contrast to apoptosis, necrosis and cell lysis causes nuclear HMGB1
to be released from cells, and this and other events stimulate the innate immune response, the recruitment of inflammatory cells, cytokine production and nuclear factor-κB (NFκB
) activation, which in some cases is linked to increased tumorigenesis27–29
. Indeed, blocking autophagy with constitutive activation of Akt in apoptosis-defective cells results in necrosis in response to metabolic stress in vitro
, and in tumours in vivo this necrosis is coincident with NF-κB activation and promotion of tumorigenesis19
. How different cell-death processes interface with the immune system and tumour micro-environment to modulate tumour growth is far from clear and is an important area for future investigation.
How defective autophagy and compromised survival to stress can promote tumour progression despite reduced cellular fitness is suggested by the increased rate of cellular damage accumulation. In tumour cells in which cell-cycle checkpoints are inactivated, autophagy limits the accumulation of genome damage and suppresses the mutation rate20,23
. This supports the role for autophagy in protecting the genome in a cell-autonomous mechanism of tumour suppression. It is currently unclear how autophagy limits genome damage, but this could involve maintaining energy homeostasis or preventing the damaging effects of oxidative stress from defective organelle and unfolded protein accumulation. As we begin to define the role of tumour cell metabolism in response to stress, the rational ability to modulate the autophagy pathway in cancer therapy is emerging.