Autophagy in tumour suppression and promotion

Abstract

Autophagy, a well-described cellular mechanism for lysosomal degradation of cytoplasmic content, has emerged as a tumour suppression pathway. Recent evidence indicates that the tumour suppressor function of autophagy is mediated by scavenging of damaged oxidative organelles, thereby preventing accumulation of toxic oxygen radicals that would cause genome instability. Paradoxically, however, in some cases autophagy can also promote the survival of cancer cells once tumours have developed. This is attributed to the ability of autophagy to promote cell survival under conditions of poor nutrient supply, as often faced by solid tumours and metastasising cancer cells. In addition, autophagy is frequently upregulated in tumours as a response to therapy and may protect tumours against therapy-induced apoptosis. In this review we discuss the mechanisms that link autophagy to tumour suppression and promotion and provide examples of the dual functions of autophagy in cancer.

Figure 1

Regulation of autophagy. Autophagy is regulated though a complex system of stimulatory and inhibitory inputs. Initiation of autophagy is dependent on class III PI 3‐kinase (PI3KC3) activation through its accessory subunits UVRAG, Beclin 1 and Bif‐1. This is negatively regulated through Beclin 1 interaction with Bcl‐2, and through JNK. Activated JNK leads to Bcl‐2 phosphorylation and Beclin 1 release and thereby promotes autophagy (Wei et al., 2008). Additional positive/negative regulation of the class III PI 3‐kinase complex is achieved by Atg14L and Rubicon binding, respectively. An important regulatory input is mediated through activated growth factor receptors, which inhibit autophagy by activating the TORC1 complex via TSC2 inhibition. Similarly, the activated RAS‐RAF pathway exerts negative control onto TSC2 via ERK. In contrast, at high AMP/ATP ratios resulting from energy depletion, the AMP‐activated kinase (AMPK) is phosphorylated by LKB1, leading to inactivation of TORC1 via TSC2 phosphorylation and activation. AMPK can also be triggered by p53, either in a positive fashion from nuclear p53, or negatively from cytosolic p53.

Figure 2

Autophagy in tumour suppression and promotion. Autophagy involves sequestration of cytoplasmic content by a double membrane, the phagophore, resulting in formation of an autophagosome. The sequestered material becomes degraded by lysosomal enzymes when the autophagosome fuses with a lysosome to yield an autolysosome. The lower part of the figure illustrates the tumour suppressive function of autophagy: If not eliminated by autophagy, damaged peroxisomes and mitochondria will cause cytosolic accumulation of reactive oxygen species (ROS), which may enter the nucleus and cause mutagenesis and genomic instability. As illustrated in the upper part of the figure, autophagy can alternatively be usurped by tumour cells to sustain survival under conditions of low nutrient supply or cytotoxic therapy.