Autophagy, Metabolism, and Cancer

  1. Eileen White1,4
  1. 1Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903
  2. 2Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901
  3. 3Department of Chemical Biology, Rutgers Ernest Mario School of Pharmacy, Piscataway, New Jersey 08854
  4. 4Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey 08854
  1. Correspondence: epwhite{at}cinj.rutgers.edu

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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