Tumor suppression and promotion by autophagy

Abstract

Autophagy is a highly regulated catabolic process that involves lysosomal degradation of proteins and organelles, mostly mitochondria, for the maintenance of cellular homeostasis and reduction of metabolic stress. Problems in the execution of this process are linked to different pathological conditions, such as neurodegeneration, aging, and cancer. Many of the proteins that regulate autophagy are either oncogenes or tumor suppressor proteins. Specifically, tumor suppressor genes that negatively regulate mTOR, such as PTEN, AMPK, LKB1, and TSC1/2 stimulate autophagy while, conversely, oncogenes that activate mTOR, such as class I PI3K, Ras, Rheb, and AKT, inhibit autophagy, suggesting that autophagy is a tumor suppressor mechanism. Consistent with this hypothesis, the inhibition of autophagy promotes oxidative stress, genomic instability, and tumorigenesis. Nevertheless, autophagy also functions as a cytoprotective mechanism under stress conditions, including hypoxia and nutrient starvation, that promotes tumor growth and resistance to chemotherapy in established tumors. Here, in this brief review, we will focus the discussion on this ambiguous role of autophagy in the development and progression of cancer.

Figure 1

Phases of autophagy and its regulation by oncogenes and tumor suppressors. In (a), the five stages of autophagy are summarized. In (b), inhibition of autophagy by oncogenes (in red) and activation by tumor suppressors (in blue) is shown. Finally, (c) summarizes details of the complex regulation and interplay between different proteins in each stage of autophagy (see text for more details).

Figure 2

The two facets of autophagy in cancer. At early stages, autophagy acts as a tumor suppressor mechanism by enhancing the degradation of damaged proteins and organelles, mostly mitochondria. In doing so, autophagy acts as a quality control system that decreases ROS production and genomic instability. Moreover, autophagy prevents necrotic cell death in apoptosis-defective cells, thereby reducing local inflammation and tumor growth. Also, autophagy may serve (in some cases) as a mechanism that leads to cell death. On the other hand, at later stages of tumor development, activation of autophagy supplies tumor cells under metabolic stress conditions with nutrients and also maintains mitochondrial metabolism by providing metabolic intermediates, which promote cell survival and tumor growth. Finally, autophagy acts as a mechanism that promotes resistance to cancer therapy.