Unique integrated stress response sensors regulate cancer cell susceptibility when Hsp70 activity is compromised
- University of Pittsburgh, United States
- Women's Cancer Research Center, UPMC Hillman Cancer Center, Magee-Women Research Institute, United States
- 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.
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All data generated or analysed during this study are included in the manuscript and source files.
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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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Unique integrated stress response sensors regulate cancer cell susceptibility when Hsp70 activity is compromised
eLife 10:e64977.
https://doi.org/10.7554/eLife.64977
