1. Cancer Biology

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

  1. Veronique Nogueira  Is a corresponding author
  2. Krushna Chandra Patra
  3. Nissim Hay  Is a corresponding author
  1. University of Illinois at Chicago, United States
https://doi.org/10.7554/eLife.32213
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  1. Veronique Nogueira
  2. Krushna Chandra Patra
  3. Nissim Hay
(2018)
Selective eradication of cancer displaying hyperactive Akt by exploiting the metabolic consequences of Akt activation
eLife 7:e32213.
https://doi.org/10.7554/eLife.32213
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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.

Article and author information

Author details

  1. 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.

  2. 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.

  3. 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.
    ORCID icon "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.

Reviewing Editor

  1. Matthew G Vander Heiden, Massachusetts Institute of Technology, United States

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.

Version history

  1. Received: September 22, 2017
  2. Accepted: April 11, 2018
  3. Accepted Manuscript published: April 24, 2018 (version 1)
  4. Accepted Manuscript updated: April 25, 2018 (version 2)
  5. Version of Record published: May 31, 2018 (version 3)

Copyright

© 2018, Nogueira et al.

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.

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  1. Veronique Nogueira
  2. Krushna Chandra Patra
  3. Nissim Hay
(2018)
Selective eradication of cancer displaying hyperactive Akt by exploiting the metabolic consequences of Akt activation
eLife 7:e32213.
https://doi.org/10.7554/eLife.32213

Share this article

https://doi.org/10.7554/eLife.32213

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