Inadequate fine-tuning of protein synthesis and failure of amino acid homeostasis following inhibition of the ATPase VCP/p97
File(s)
Accepted version
Published version
Author(s)
Type
Journal Article
Abstract
The cellular mechanisms that control protein degradation may constitute a non-oncogenic cancer cell vulnerability and, therefore, a therapeutic target. Although this proposition is supported by the clinical success of proteasome inhibitors in some malignancies, most cancers are resistant to proteasome inhibition. The ATPase valosin-containing protein (VCP; p97) is an essential regulator of protein degradation in multiple pathways and has emerged as a target for cancer therapy. We found that pharmacological depletion of VCP enzymatic activity with mechanistically different inhibitors robustly induced proteotoxic stress in solid cancer and multiple myeloma cells, including cells that were insensitive, adapted, or clinically resistant to proteasome inhibition. VCP inhibition had an impact on two key regulators of protein synthesis, eukaryotic initiation factor 2α (eIF2α) and mechanistic target of rapamycin complex 1 (mTORC1), and attenuated global protein synthesis. However, a block on protein translation that was itself cytotoxic alleviated stress signaling and reduced cell death triggered by VCP inhibition. Some of the proteotoxic effects of VCP depletion depended on the eIF2α phosphatase, protein phosphatase 1 regulatory subunit 15A (PPP1R15A)/PP1c, but not on mTORC1, although there appeared to be cross-talk between them. Thus, cancer cell death following VCP inhibition was linked to inadequate fine-tuning of protein synthesis and activity of PPP1R15A/PP1c. VCP inhibitors also perturbed intracellular amino acid levels, activated eukaryotic translation initiation factor 2α kinase 4 (EIF2AK4), and enhanced cellular dependence on amino acid supplies, consistent with a failure of amino acid homeostasis. Many of the observed effects of VCP inhibition differed from the effects triggered by proteasome inhibition or by protein misfolding. Thus, depletion of VCP enzymatic activity triggers cancer cell death in part through inadequate regulation of protein synthesis and amino acid metabolism. The data provide novel insights into the maintenance of intracellular proteostasis by VCP and may have implications for the development of anti-cancer therapies.
Date Issued
2015-12-31
Date Acceptance
2015-11-19
Citation
Cell Death & Disease, 2015, 6
ISSN
2041-4889
Publisher
Nature Publishing Group
Journal / Book Title
Cell Death & Disease
Volume
6
Copyright Statement
© 2015 The Authors. Cell Death and Disease is an open-access journal
published by Nature Publishing Group. This work is
licensed under a Creative Commons Attribution 4.0 International
License. The images or other third party material in this article are
included in the article’s Creative Commons license, unless indicated
otherwise in the credit line; if the material is not included under the
Creative Commons license, users will need to obtain permission from
the license holder to reproduce the material. To view a copy of this
license, visit http://creativecommons.org/licenses/by/4.0/
published by Nature Publishing Group. This work is
licensed under a Creative Commons Attribution 4.0 International
License. The images or other third party material in this article are
included in the article’s Creative Commons license, unless indicated
otherwise in the credit line; if the material is not included under the
Creative Commons license, users will need to obtain permission from
the license holder to reproduce the material. To view a copy of this
license, visit http://creativecommons.org/licenses/by/4.0/
License URL
Sponsor
Imperial College Healthcare NHS Trust- BRC Funding
WELLCOME TRUST
CRUK
Grant Number
RDB05 79560
NCC3200/CHINN/GENTLEMAN
C41494/A15448
Publication Status
Published
Article Number
e2031