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Published online 11 December 2006. doi:10.1083/jcb.200512100
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 175, Number 6, 913-923
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Article

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

Hélène Pelicano1, Rui-hua Xu1,5, Min Du4, Li Feng1, Ryohei Sasaki1, Jennifer S. Carew1, Yumin Hu1, Latha Ramdas2, Limei Hu2, Michael J. Keating3, Wei Zhang2, William Plunkett4, and Peng Huang1

Departments of 1 Molecular Pathology, 2 Pathology, 3 Leukemia, and 4 Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030
5 Department of Medical Oncology, Sun-Yat Sen University Cancer Center, Guangzhou 510060, China

Correspondence to Peng Huang: phuang{at}mdanderson.org

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 ({rho}-) 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.

R. Sasaki's current address is Division of Radiology, Kobe Graduate School of Medicine, Kobe City, Hyogo 650-0017, Japan.

Abbreviations used in this paper: GSK, glycogen synthase kinase; mtDNA, mitochondrial DNA; NAC, N-acetylcysteine; PI, propidium iodide; PI3K, phosphatidylinositol 3-kinase; PIP3, phosphatidylinositol-3'-phosphate; PPP, pentose phosphate pathway; ROS, reactive oxygen species; Trx, thioredoxin.


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