Selective eradication of cancer displaying hyperactive Akt by exploiting the metabolic consequences of Akt activation

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Abstract

Akt activation in human cancers exerts chemoresistance, but pan-Akt inhibition elicits adverse consequences. We exploited the consequences of Akt-mediated mitochondrial and glucose metabolism to selectively eradicate and evade chemoresistance of prostate cancer displaying hyperactive Akt. PTEN-deficient prostate cancer cells that display hyperactivated Akt have high intracellular reactive oxygen species (ROS) levels, which are due, in part, to Akt-dependent increase of oxidative phosphorylation. High intracellular ROS levels selectively sensitize cells displaying hyperactive Akt to ROS-induced cell death enabling a therapeutic strategy combining a ROS inducer and rapamycin in PTEN-deficient prostate tumors in mouse models. This strategy elicited tumor regression, and markedly increased survival even after the treatment was stopped. By contrast, exposure to antioxidant increased prostate tumor progression. To increase glucose metabolism Akt activation phosphorylates HK2 and induced its expression. Indeed, HK2 deficiency in mouse models of Pten-deficient prostate cancer elicited a marked inhibition of tumor development and extended lifespan.

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Veronique Nogueira

Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, United States

For correspondence
vnogueir@uic.edu

Competing interests
The authors declare that no competing interests exist.
Krushna Chandra Patra

Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, United States

Competing interests
The authors declare that no competing interests exist.
Nissim Hay

Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, United States

For correspondence
nhay@uic.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-6245-3000

Funding

National Institutes of Health (R01AG016927)

Nissim Hay

VA (BX000733)

Nissim Hay

National Institutes of Health (R01 CA090764)

Nissim Hay

National Institutes of Health (R01 CA206167)

Nissim Hay

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animal experimentation: Mice were maintained and handled in accordance with the Animal Care Policies of the University of Illinois at Chicago and studies were approved by Animal Care and Use Committee under protocol numbers 13-036 and 14-112.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.