Autophagy, Metabolism, and Cancer

By E. White, J. Mehnert, Chang S. Chan. Clinical Cancer Research, 2015

763 citations recorded by the source corpus.

Macroautophagy (autophagy hereafter) captures intracellular proteins and organelles and degrades them in lysosomes. The degradation breakdown products are released from lysosomes and recycled into metabolic and biosynthetic pathways. Basal autophagy provides protein and organelle quality control by eliminating damaged cellular components. Starvation-induced autophagy recycles intracellular components into metabolic pathways to sustain mitochondrial metabolic function and energy homeostasis. Recycling by autophagy is essential for yeast and mammals to survive starvation through intracellular nutrient scavenging. Autophagy suppresses degenerative diseases and has a context-dependent role in cancer. In some models, cancer initiation is suppressed by autophagy. By preventing the toxic accumulation of damaged protein and organelles, particularly mitochondria, autophagy limits oxidative stress, chronic tissue damage, and oncogenic signaling, which suppresses cancer initiation. This suggests a role for autophagy stimulation in cancer prevention, although the role of autophagy in the suppression of human cancer is unclear. In contrast, some cancers induce autophagy and are dependent on autophagy for survival. Much in the way that autophagy promotes survival in starvation, cancers can use autophagy-mediated recycling to maintain mitochondrial function and energy homeostasis to meet the elevated metabolic demand of growth and proliferation. Thus, autophagy inhibition may be beneficial for cancer therapy. Moreover, tumors are more autophagy-dependent than normal tissues, suggesting that there is a therapeutic window. Despite these insights, many important unanswered questions remain about the exact mechanisms of autophagy-mediated cancer suppression and promotion, how relevant these observations are to humans, and whether the autophagy pathway can be modulated therapeutically in cancer. Clin Cancer Res; 21(22); 5037–46. ©2015 AACR. See all articles in this CCR Focus section, “Cell Death and Cancer Therapy.”

Subfields: Cell Biology, Epidemiology, Pharmacology

View Paper: https://www.semanticscholar.org/paper/041628da0da5c9844bb2010a89b31ac838c17b1e

How researchers see this paper

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In Cell Biology

1. Alec C. Kimmelman
2. E. White

In Epidemiology

1. Alec C. Kimmelman
2. R. Amaravadi
3. E. White
4. Guido Kroemer
5. Beth Levine
6. Chang S. Chan
7. J. Mehnert
8. Y. Fouad

In Pharmacology

1. R. Amaravadi
2. E. White
3. Alec C. Kimmelman

Citations in the corpus

• Recent insights into the function of autophagy in cancer (2016, background): “Genomic analysis of BECN1 in The Cancer Genome Atlas (TCGA) demonstrated that allelic loss of BECN1 does not occur independently of codeletion with BRCA1, suggesting that BRCA1 loss is the driver mutation in hereditary and sporadic breast cancer (Laddha et al. 2014; White et al. 2015).”
• How Do Cytotoxic Lymphocytes Kill Cancer Cells? (2015, background): “At present, it is unknown whether other mechanism of cell death and/or survival such pyroptosis, necroptosis (3), or autophagy (100) may regulate cell death executed by CL.”
• Autophagy and Tumor Metabolism (2017, background): “Given the diverse substrates that can be degraded via autophagy, it is not surprising that autophagy has the potential to fuel nearly all aspects of central carbon metabolism (Guo and White, 2017; Rabinowitz and White, 2010) (Figure 1).”