Autophagy and Tumor Metabolism

Abstract

Autophagy is a critical cellular process that generally protects cells and organisms from stressors such as nutrient deprivation. In addition to its role in normal physiology, autophagy plays a role in pathological processes such as cancer. Indeed, there has been substantial work exploring the complex and context-dependent role of autophagy in cancer. One of the emerging themes is that in certain cancer types, autophagy is important to support tumor growth; therefore, inhibiting autophagy as a therapeutic approach is actively being tested in clinical trials. A key mechanism of how autophagy promotes the growth and survival of various cancers is its ability to support cellular metabolism. The diverse metabolic fuel sources that can be produced by autophagy provide tumors with metabolic plasticity and can allow them to thrive in what can be an austere microenvironment. Therefore, understanding how autophagy can fuel cellular metabolism will enable more effective combinatorial therapeutic strategies.

Figure 1

The process of autophagy leads to the degradation of cargo which amongst other functions serves to maintain organelle quality control (mitochondria as an example via mitophagy) as well as produce a variety of substrates to fuel cellular metabolism. This can help promote proliferation and survival of tumors during stressors such as hypoxia, redox stress, nutrient limitation, and a variety of anti-cancer therapies. The blue double-membraned vesicle -autophagosome; red vesicle – lysosome; blue shaded oval structure – nucleus; cargo in the autophagosome (mitochondria in yellow, protein aggregates in black and red, other cargo is generally represented in green and purple).

Figure 2

Autophagy inhibition in the tumor cells can disrupt tumor metabolism leading to a variety of metabolic consequences including impaired mitochondrial metabolism, redox imbalance, depletion of nucleotide pools, and a decrease in energy charge. In certain settings, this can lead to an impairment in tumor growth as well as tumor cell death. Similarly, systemic autophagy inhibition may have anti-tumor effects through both the aforementioned tumor cell autonomous effects as well as its impact on the tumor microenvironment, host metabolism, and disruption of metabolic cross-talk circuits between tumor and stroma cells. Impairment of these can also lead to a disruption of tumor growth.