Unique integrated stress response sensors regulate cancer cell susceptibility when Hsp70 activity is compromised

  1. Sara Sannino  Is a corresponding author
  2. Megan E Yates
  3. Mark E Schurdak
  4. Steffi Oesterreich
  5. Adrian V Lee
  6. Peter Wipf
  7. Jeffrey L Brodsky  Is a corresponding author
  1. University of Pittsburgh, United States
  2. Women's Cancer Research Center, UPMC Hillman Cancer Center, Magee-Women Research Institute, United States
  3. Institute for Precision Medicine, United States

Abstract

Molecular chaperones, such as Hsp70, prevent proteotoxicity and maintain homeostasis. This is perhaps most evident in cancer cells, which overexpress Hsp70 and thrive even when harboring high levels of misfolded proteins. To define the response to proteotoxic challenges, we examined adaptive responses in breast cancer cells in the presence of an Hsp70 inhibitor. We discovered that the cells bin into distinct classes based on inhibitor sensitivity. Strikingly, the most resistant cells have higher autophagy levels, and autophagy was maximally activated only in resistant cells upon Hsp70 inhibition. In turn, resistance to compromised Hsp70 function required the integrated stress response transducer, GCN2, which is commonly associated with amino acid starvation. In contrast, sensitive cells succumbed to Hsp70 inhibition by activating PERK. These data reveal an unexpected route through which breast cancer cells adapt to proteotoxic insults and position GCN2 and autophagy as complementary mechanisms to ensure survival when proteostasis is compromised.

Data availability

All data generated or analysed during this study are included in the manuscript and source files.

Article and author information

Author details

  1. Sara Sannino

    Department of Biological Sciences, University of Pittsburgh, Pittsburgh, United States
    For correspondence
    sannino.sara1986@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
  2. Megan E Yates

    Department of Biological Sciences, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Mark E Schurdak

    Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Steffi Oesterreich

    Women's Cancer Research Center, UPMC Hillman Cancer Center, Magee-Women Research Institute, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Adrian V Lee

    Institute for Precision Medicine, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Peter Wipf

    Department of Chemistry, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Jeffrey L Brodsky

    Department of Biological Sciences, University of Pittsburgh, Pittsburgh, United States
    For correspondence
    jbrodsky@pitt.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6984-8486

Funding

European Molecular Biology Laboratory (post-doctoral fellowship (ALTF 823-2016))

  • Sara Sannino

National Institutes of Health (F30CA250167)

  • Megan E Yates

National Institutes of Health (GM131732)

  • Jeffrey L Brodsky

National Institutes of Health (DK79307)

  • Jeffrey L Brodsky

National Institutes of Health (P30CA047904)

  • Jeffrey L Brodsky

Howard Hughes Medical Institute (Howard Hughes Medical Institute Collaborative Innovation award)

  • Jeffrey L Brodsky

University of Pittsburgh (Translational and Precision Pharmacology programs (pilot grant))

  • Jeffrey L Brodsky

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

Copyright

© 2021, Sannino 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. Sara Sannino
  2. Megan E Yates
  3. Mark E Schurdak
  4. Steffi Oesterreich
  5. Adrian V Lee
  6. Peter Wipf
  7. Jeffrey L Brodsky
(2021)
Unique integrated stress response sensors regulate cancer cell susceptibility when Hsp70 activity is compromised
eLife 10:e64977.
https://doi.org/10.7554/eLife.64977

Share this article

https://doi.org/10.7554/eLife.64977

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