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Deconvoluting the context-dependent role for autophagy in cancer

Nature Reviews Cancer volume 12, pages 401–410 (2012)Cite this article

Subjects

Key Points

  • Autophagy is a cellular self-cannibalization process that captures and digests cellular proteins and organelles in lysosomes.

  • Autophagy levels are normally low but are dramatically induced by starvation and stress.

  • Recycling of cellular material by autophagy sustains cellular and mammalian metabolism necessary for survival in starvation.

  • The elimination of damaged proteins and organelles by autophagy is required for cellular homeostasis.

  • Autophagy can be tumour suppressive by preventing chronic tissue damage and cancer initiation.

  • Autophagy is induced in and required for the survival of tumour cells in hypoxic tumour regions.

  • Many cancer cells upregulate autophagy that is required to support metabolism, tumorigenesis and survival to therapy.

  • In aggressive cancers, autophagy inhibition may be therapeutically advantageous.

Abstract

Autophagy (also known as macroautophagy) captures intracellular components in autophagosomes and delivers them to lysosomes, where they are degraded and recycled. Autophagy can have two functions in cancer. It can be tumour suppressive through the elimination of oncogenic protein substrates, toxic unfolded proteins and damaged organelles. Alternatively, it can be tumour promoting in established cancers through autophagy-mediated intracellular recycling that provides substrates for metabolism and that maintains the functional pool of mitochondria. Therefore, defining the context-specific role for autophagy in cancer and the mechanisms involved will be important to guide autophagy-based therapeutic intervention.

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Figure 1: Regulation of NRF2 by autophagy, KEAP1 and p62.
Figure 2: Mechanism of autophagy-mediated tumour suppression.
Figure 3: The role of autophagy in supporting the growth of aggressive cancers.
Figure 4: Mechanism of autophagy addiction of RAS-driven cancers.

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Acknowledgements

I thank members of the White laboratory for helpful discussions and advice. This work was supported by grants from the US National Institutes of Health (R37 CA53370, RO1 CA130893 and RC1 147961), DOD (W81XWH06-1-0514 and W81XWH05) and the V Foundation.

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  1. The Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, 08903, New Jersey, USA

    Eileen White

  2. University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, 08854, New Jersey, USA

    Eileen White

  3. Department of Molecular Biology and Biochemistry, Rutgers University, 604 Allison Road, Piscataway, 08854, New Jersey, USA

    Eileen White

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Glossary

Tricarboxylic acid (TCA) cycle

Also known as the citric acid cycle or the Krebs cycle, the TCA cycle is a series of chemical reactions that generate energy and building blocks through the oxidation of acetate derived from carbohydrates, fats and proteins into carbon dioxide and water.

Reactive oxygen species

(ROS). Chemically reactive molecules containing oxygen that cause cellular damage or that activate signalling.

Steatohepatitis

A pathological condition, also known as fatty liver disease, characterized by inflammation and fat accumulation in the liver.

Proteasome

A large protein complex responsible for the degradation of soluble proteins.

NF-κB

A transcription factor that controls the immune response to damage and infection.

mTOR

A serine/threonine protein kinase that regulates cell growth, cell proliferation, cell survival, protein synthesis and transcription in response to nutrient and growth factor availability.

Hypoxia

A pathological condition in which the body as a whole or a region of the body, such as a tumour, is deprived of an adequate oxygen supply.

Cataplerosis

The process by which metabolic intermediates are removed from metabolic pathways.

Glycolysis

The metabolic pathway that converts glucose into pyruvate and in the process produces ATP and reduced NADH.

Glutaminolysis

A series of biochemical reactions in which the amino acid glutamine is degraded to glutamate then to α-ketoglutarate for further metabolism in the tricarboxylic acid cycle.

Anaplerosis

The process of replenishment of depleted metabolic cycle or pathway intermediates.

ER stress

A stress adaptation pathway activated by the accumulation of unfolded proteins in the endoplasmic reticulum (ER).

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White, E. Deconvoluting the context-dependent role for autophagy in cancer. Nat Rev Cancer 12, 401–410 (2012). https://doi.org/10.1038/nrc3262

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