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Review
. 2016:81:73-78.
doi: 10.1101/sqb.2016.81.030981. Epub 2017 Feb 16.

Autophagy, Metabolism, and Cancer

Jessie Yanxiang Guo  1   2   3 , Eileen White  1   4
Affiliations
Review

Autophagy, Metabolism, and Cancer

Jessie Yanxiang Guo et al. Cold Spring Harb Symp Quant Biol. 2016.

Abstract

Macroautophagy (autophagy hereafter) is a process that collects cytoplasmic components, particularly mitochondria, and degrades them in lysosomes. In mammalian systems, basal autophagy levels are normally low but are profoundly stimulated by starvation and essential for survival. Cancer cells up-regulate autophagy and can be more autophagy-dependent than most normal tissues. Genetic deficiency in essential autophagy genes in tumors in many autochthonous mouse models for cancer reduces tumor growth. In K-rasG12D-driven non-small cell lung cancer (NSCLC) and other models, autophagy sustains metabolism and survival. The mechanism by which autophagy promotes tumorigenesis varies in different contexts, but evidence points to a critical role for autophagy in sustaining metabolism, thereby preventing p53 activation, energy crisis, growth arrest, apoptosis, senescence, and activation of the immune response. Autophagy in NSCLC preserves mitochondrial quality and regulates their abundance. By degrading macromolecules in lysosomes, autophagy provides mitochondria with substrates to prevent energy crisis and fatal nucleotide pool depletion in starvation. We review here how autophagy supports mammalian survival and how cancer cells usurp this survival mechanism to maintain mitochondrial metabolism for their own benefit. Insights from these studies provide the rationale and approach to target the autophagy survival pathway for cancer therapy.

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Conflict of interest statement

DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

E.W. is on the Scientific Advisory Board of Forma Therapeutics.

Figures

Figure 1
Figure 1
Mechanism by which autophagy promotes the survival of adult mice during fasting. During fasting, healthy adult mice activate autophagy and degrade glycogen to maintain circulating glucose and mobilize lipid stores to produce glycerol and fatty acids for ketogenesis and gluconeogenesis. As a last resort, muscle degradation by atrophy-associated E3 ligases may supply amino acids for ketogenesis and gluconeogenesis (Karsli-Uzunbas et al. 2014). As a result, glucose homeostasis is maintained by autophagy in mice to surviving fasting. However, fasting adult mice with acute autophagy ablation causes excessive depletion of nutrient stores including lipid and glycogen, accelerated muscle catabolism, and liver damage, which causes severe systemic hypoglycemia, brain damage, and mouse death. (Modified, with permission, from Karsli-Uzunbas et al. 2014, © AACR.)
Figure 2
Figure 2
Defective autophagy in tumor cells alters metabolic flux from glutamine to aspartate and to de novo nucleotide synthesis. K-ras-driven tumor cells depend on autophagy to supply the substrate glutamine and its derivatives to sustain mitochondria metabolism for starvation survival. To compensate, Atg7-deficient tumor cells significantly increase glutamine flux to the tricarboxylic acid (TCA) cycle, de novo nucleotide synthesis, and nicotinamide adenine dinucleotide phosphate (NADPH) generation by up-regulating flux from malate, pyruvate, acetyl-CoA, and citrate for antioxidant defense (Guo et al. 2016). OAA, oxaloacetate; α-KG, α-ketogluturate.
Figure 3
Figure 3
Autophagy recycles macromolecules to provide mitochondrial substrates for nucleotide synthesis and energy homeostasis. Tumor cells rely on mitochondria metabolism for their proliferation and tumorigenesis. In starvation, autophagy is essential to mediate substrate recycling to supply tricarboxylic acid (TCA)-associated amino acids, which are further metabolized through the TCA cycle for energy production and de novo nucleotide biosynthesis. OAA, oxaloacetate; ETC, electron transport chain.
Figure 4
Figure 4
Autophagy-supplied substrates prevent energy crisis and fatal nucleotide depletion. Substrates derived from autophagy are required to generate ATP via tricarboxylic acid (TCA) cycle–driven oxidative phosphorylation in starvation. In the absence of autophagy, defective de novo nucleotide synthesis and increased nucleotide degradation cause nucleotide pool depletion and cell death.
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