Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2013 Oct;9(10):1636-8.
doi: 10.4161/auto.26123. Epub 2013 Aug 15.

Autophagy is required for mitochondrial function, lipid metabolism, growth, and fate of KRAS(G12D)-driven lung tumors

Jessie Yanxiang Guo  1 , Eileen White  1
Affiliations
Review

Autophagy is required for mitochondrial function, lipid metabolism, growth, and fate of KRAS(G12D)-driven lung tumors

Jessie Yanxiang Guo et al. Autophagy. 2013 Oct.

Abstract

Evidence suggests that the role of autophagy in tumorigenesis is context dependent. Using genetically engineered mouse models (GEMMs) for human non-small-cell lung cancer (NSCLC), we found that deletion of the essential autophagy gene, Atg7, in KRAS(G12D)-driven NSCLC inhibits tumor growth and converts adenomas and adenocarcinomas to benign oncocytomas characterized by the accumulation of respiration-defective mitochondria. Atg7 is required to preserve mitochondrial fatty acid oxidation (FAO) to maintain lipid homeostasis upon additional loss of Trp53 in NSCLC. Furthermore, cell lines derived from autophagy-deficient tumors depend on glutamine to survive starvation. This suggests that autophagy is essential for the metabolism, growth, and fate of NSCLC.

Keywords: KRAS; NSCLC; autophagy; fatty acid oxidation; metabolism; mitochondria; oncocytoma; p53.

PubMed Disclaimer

Figures

None
Figure 1. Autophagy maintains functioning mitochondria to support KRASG12D-driven NSCLC tumor metabolism, growth, and fate. (A) When Trp53 is intact in KRASG12D-driven NSCLC, Atg7 deficiency causes accumulation of dysfunctional mitochondria and converts adenomas and adenocarcinomas to oncocytomas, which results in tumor growth arrest and tumor atrophy. (B) With the additional loss of Trp53, Atg7 deficiency still converts adenocarcinomas to oncocytomas, but also causes defective mitochondrial FAO, leading to tumor cell lipid accumulation and metabolic impairment. (C) Tumor cell metabolism regulated by autophagy is oncogene- and tumor suppressor gene-dependent: with the additional loss of Trp53, autophagy preserves mitochondrial FAO and may provide metabolic substrates such as glutamine from protein degradation. RAS-driven cancer cells increase glucose metabolism to support their high energetic and biosynthetic demands. Increased glycolysis enhances conversion of pyruvate to lactate, resulting in insufficient pyruvate to support mitochondrial tricarboxylic acid (TCA) cycle metabolism upon nutrient deprivation. In this case, activated autophagy will degrade proteins and organelles to supply glutamine to maintain mitochondrial metabolism and FAO. When autophagy is blocked, however, depletion of the metabolic substrate glutamine, important for TCA cycle anaplerosis and defective FAO, will lead to tumor cell metabolic catastrophe.
See this image and copyright information in PMC

Comment on

  • Guo JY, Karsli-Uzunbas G, Mathew R, Aisner SC, Kamphorst JJ, Strohecker AM, Chen G, Price S, Lu W, Teng X, et al. . Autophagy suppresses progression of K-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis Genes Dev 2013 27 1447 61 http://dx.doi.org/10.1101/gad.219642.113 PMID:

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

Publication types