Mitochondrial respiration defects in cancer cells cause activation of Akt survival pathway through a redox-mediated mechanism

Cancer cells exhibit increased glycolysis for ATP production due, in part, to respiration injury (the Warburg effect). Because ATP generation through glycolysis is less efficient than through mitochondrial respiration, how cancer cells with this metabolic disadvantage can survive the competition wit...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of cell biology 2006-12, Vol.175 (6), p.913-923
Main Authors: Pelicano, Hélène, Xu, Rui-hua, Du, Min, Feng, Li, Sasaki, Ryohei, Carew, Jennifer S, Hu, Yumin, Ramdas, Latha, Hu, Limei, Keating, Michael J, Zhang, Wei, Plunkett, William, Huang, Peng
Format: Article
Language:English
Subjects:
Adenosine triphosphatase
Apoptosis
Cancer
Cell Hypoxia
Cell Respiration - physiology
Cell Survival
Cells
DNA, Mitochondrial - genetics
DNA, Mitochondrial - metabolism
Enzyme Activation
Glycolysis - physiology
Humans
Kinases
Mitochondria - metabolism
NAD
Neoplasms - metabolism
Oxidation-Reduction
Phosphatidylinositol 3-Kinases - metabolism
Phosphorylation
Proto-Oncogene Proteins c-akt - metabolism
PTEN Phosphohydrolase - genetics
PTEN Phosphohydrolase - metabolism
Signal Transduction
Tumor Cells, Cultured
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Cancer cells exhibit increased glycolysis for ATP production due, in part, to respiration injury (the Warburg effect). Because ATP generation through glycolysis is less efficient than through mitochondrial respiration, how cancer cells with this metabolic disadvantage can survive the competition with other cells and eventually develop drug resistance is a long-standing paradox. We report that mitochondrial respiration defects lead to activation of the Akt survival pathway through a novel mechanism mediated by NADH. Respiration-deficient cells (ρ⁻) harboring mitochondrial DNA deletion exhibit dependency on glycolysis, increased NADH, and activation of Akt, leading to drug resistance and survival advantage in hypoxia. Similarly, chemical inhibition of mitochondrial respiration and hypoxia also activates Akt. The increase in NADH caused by respiratory deficiency inactivates PTEN through a redox modification mechanism, leading to Akt activation. These findings provide a novel mechanistic insight into the Warburg effect and explain how metabolic alteration in cancer cells may gain a survival advantage and withstand therapeutic agents.
ISSN:0021-9525
1540-8140
DOI:10.1083/jcb.200512100