ATG12 deficiency leads to tumor cell oncosis owing to diminished mitochondrial biogenesis and reduced cellular bioenergetics

In contrast to the "Warburg effect" or aerobic glycolysis earlier generalized as a phenomenon in cancer cells, more and more recent evidence indicates that functional mitochondria are pivotal for ensuring the energy supply of cancer cells. Here, we report that cancer cells with reduced aut...

Full description

Saved in:
Bibliographic Details
Published in:Cell death and differentiation Vol. 27; no. 6; pp. 1965 - 1980
Main Authors: Liu, He, He, Zhaoyue, Germič, Nina, Ademi, Hyrijie, Frangež, Živa, Felser, Andrea, Peng, Shuang, Riether, Carsten, Djonov, Valentin, Nuoffer, Jean-Marc, Bovet, Cédric, Mlinarič-Raščan, Irena, Zlobec, Inti, Fiedler, Martin, Perren, Aurel, Simon, Hans-Uwe
Format: Journal Article
Language:English
Published: England Nature Publishing Group 01.06.2020
Subjects:
Apoptosis
Autophagy
Bioenergetics
Biosynthesis
Cancer
Caspase
Cell death
Energy metabolism
Glycolysis
Hexokinase
Immune system
Metabolomics
Mitochondria
Mitochondrial DNA
Mitochondrial uncoupling protein 2
Oxidation
Phagocytosis
Phenotypes
Solid tumors
Tricarboxylic acid cycle
Tumors
Xenografts
ISSN:1350-9047, 1476-5403, 1476-5403
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:In contrast to the "Warburg effect" or aerobic glycolysis earlier generalized as a phenomenon in cancer cells, more and more recent evidence indicates that functional mitochondria are pivotal for ensuring the energy supply of cancer cells. Here, we report that cancer cells with reduced autophagy-related protein 12 (ATG12) expression undergo an oncotic cell death, a phenotype distinct from that seen in ATG5-deficient cells described before. In addition, using untargeted metabolomics with ATG12-deficient cancer cells, we observed a global reduction in cellular bioenergetic pathways, such as β-oxidation (FAO), glycolysis, and tricarboxylic acid cycle activity, as well as a decrease in mitochondrial respiration as monitored with Seahorse experiments. Analyzing the biogenesis of mitochondria by quantifying mitochondrial DNA content together with several mitochondrion-localizing proteins indicated a reduction in mitochondrial biogenesis in ATG12-deficient cancer cells, which also showed reduced hexokinase II expression and the upregulation of uncoupling protein 2. ATG12, which we observed in normal cells to be partially localized in mitochondria, is upregulated in multiple types of solid tumors in comparison with normal tissues. Strikingly, mouse xenografts of ATG12-deficient cells grew significantly slower as compared with vector control cells. Collectively, our work has revealed a previously unreported role for ATG12 in regulating mitochondrial biogenesis and cellular energy metabolism and points up an essential role for mitochondria as a failsafe mechanism in the growth and survival of glycolysis-dependent cancer cells. Inducing oncosis by imposing an ATG12 deficiency in solid tumors might represent an anticancer therapy preferable to conventional caspase-dependent apoptosis that often leads to undesirable consequences, such as incomplete cancer cell killing and a silencing of the host immune system.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 14
content type line 23
ISSN:1350-9047
1476-5403
1476-5403
DOI:10.1038/s41418-019-0476-5